] Disorders of Hemostasis

Disorders of Hemostasis Dr. Batizy 11/2/06 Primary Hemostasis • The platelet contains lysosomes, granules, and trilaminar plasma membrane, microtubules. • Granules are key in primary hemostasis and contain ADP, Thromboxane, platelet factor 4, adhesive and aggregation glycoproteins, coagulation factors, and fibrinolytic inhibitors Primary Hemostasis • Dependent on Platelets and Von Willebrand Factor (vWF) • Platelets gather and attach to vWF • Platelets degranulate after attachment and release ADP and Thromboxane which attracts more platelets • Forms a platelet plug • Requires endothelial damage to adhere Secondary Hemostasis • Platelet aggregation initiates secondary hemostasis through the coagulation cascade • Coagulation cascade is initiated by the intrinsic or extrinsic pathway • The final cascade results in fibrin deposition cross-linking platelets and clot formation The Coagulation Cascade Common Pathway A word on clotting factors • Vitamin K Dependent Factors – Intrinsic Pathway : IX, X – Common Pathway: II – Extrinsic Pathway: VII • All clotting Factors are produced in liver except vWF/VIII • VIII produced by the vascular endothelium • Sites of heparin activity – IIa, IXa, Xa ( major site), XIa, Platelet factor 3 A word on clotting factors • Factor VIII – A factor by any other name? – Same factor: 3 different activities – VIII:C – antihemophilic or coagulation activity – vWF – supports platelet adhesion and carries VIII in the blood – VIII:Ag – reacts with rabbit antibodies, relates to measured plasma level rather than activity Fibrinolysis • The Ying to the Yang of clot formation • Tissue Plasminogen activator (tPA) – Released from endothelial cells • Converts plasminogen to plasmin which degrades fibrinogen and fibrin into fibrin degradation products • Cross linked fibrin is cleaved into DDimers Testing the hemostatic system • CBC – H/H drops often lag behind actual RBC loss due to slow equilibration • Blood smear – Schistocytes and fragemented RBC- DIC – Teardrop-shaped or nucleated RBC – Myelophthisic disease – Characteristic WBC morphologies seen in thrombocytopenia in infectious mononucleosus, folate, B12 deficiency, or leukemia Testing the hemostatic system • Platelet count – Thrombocytopenia : Less that 100,000/mL – Spontaneous bleeding possible: Less than 20,000/mL – Count does not have anything to do with functionality of platelet Testing the hemostatic system • Bleeding time – Tests vascular integrity and platelet function – Incision on volar aspect of the forearm 1mm deep and 1 cm long – BP cuff inflated to 40 mmHg – Normal < 8 minutes – Borderline 8-10 minutes – Abnormal 10 + minutes – Affected by ASA (permanent) and NSAIDs Testing the hemostatic system • Bleeding time – Prolonged with platelet counts below 100,000 – When prolonged with platelet count over 100,000 suggests platelet dysfunction Testing the hemostatic system • Prothrombin Time – Test of extrinsic and common pathways – International Normalized Ratio used to compensate for differences in thromboplastin reagents – Used for coumadin – Elevated in patients with liver disease and abnormalities in vitamin K sensitive factors Testing the hemostatic system • Partial Thromboplastin Time (PTT) – Tests intrinsic and common pathway – Average normal 25-29 – Factor levels usually less than 40% to be affected – Affected by heparin – Can be effected by coumadin at supratherapeutic levels due to effects on the common pathway History and Physical • Platelet Disorders – More common in Women – Petechiae, Purpura, mucosal bleeding • Coagulation Disorder – More common in Men – More commonly acquired – Delayed deep muscle bleeding, hemarthrosis, hematuria – More commonly congenital Thrombocytopenia • Usually mucosal bleeding • Epistaxis, menorrhagia, and GI bleeding is common • Trauma does not usually cause bleeding Thrombocytopenia • Three mechanisms of Thrombocytopenia – Decreased production • Usually chemotherapy, myelophthisic disease, or BM effects of alcohol or thiazides – Splenic Sequesteration • Rare • Results from malignancy, portal hypertension, or increased Splenic RBC destruction ( hereditary spherocytosis, autoimmune hemolytic anemia) – Increased Destruction Thrombocytopenia • Immune thrombocytopenia – Multiple causes including drugs, lymphoma, leukemia, collagen vascular disease – Drugs Include • Digitoxin, sulfonamindes, phenytoin, heparin, ASA, cocaine, Quinine, quinidine, glycoprotein IIb-IIa antagonists – After stopping drugs platelet counts usually improve over 3 to 7 days – Prednisone (1mg/kg) with rapid taper can shorten course Thrombocytopenia • HIT – Important Immunologic Thrombocytopenia – Usually within 5-7 days of Initiation of Heparin Therapy but late onset cases are 14-40 days – Occurrence 1-5% with unfractionated heparin and less than 1% with low molecular-weight heparin – Thrombotic complications in up to 50% of HIT with loss of limb in 20% and mortality up to 30% ITP • Diagnosis of exclusion • Associated with IgG anti-platelet antibody • Platelet count falls to less that 20,000 ITP • Acute Form – Most common in children 2 to 6 years – Viral Prodrome common in the 3 weeks prior – Self Limited and > 90% remission rate – Supportive Treatment – Steroids are not helpful ITP • Chronic Form – Adult disease primarily – Women more often than men – Insidious onset with no prodrome – Symptoms include: easy bruising, prolonged menses, mucosal bleeding – Bleeding complications are unpredictable – Mortality is 1% – Spontaneous remission is rare ITP • Chronic Form – Hospitalization common because of a complex differential diagnosis – Multiple treatments – Platelet transfusions are used only for life threatening bleeding – Life threatening bleeding is treated with IV Immune globulin (1g/kg) TTPHUS • Exist on a continuum and are likely the same disease • Diagnosed by a common pentad – Microangiopathic Hemolytic Anemia: Schistocytes membranes are sheared passing through microthrombi – Thrombocytopenia: More sever in TTP – Fever – Renal Abnormalities: More prominent in HUS: include Renal insufficiency, azotemia, proteinuria, hematuria, and renal failure – Neurologic Abnormalities: hallmark of TTP 1/3 of HUS: Sx of HA, confusion, CN palsies, seizure,coma TTPHUS • Labs – PT, PTT, and fibrinogen are within reference range – Helmet Cells (Shistocytes) are common TTPHUS • HUS – Most common in infants and children 6mo - 4 years – Often associated with a prodromal diarrhea – Strongest association to E. coli O157:H7 but also associated with SSYC as well as multiple virus – Prognosis • Mortality 5-15% • Younger patients do better TTPHUS • HUS – Treatment • • • • Mostly supportive Plasma exchange reserved for sever cases Treat hyperkalemia Avoid antibiotics with Ecoli – May actually increase verotoxin production with TMPSMX – May be helpful with cases of Shigella dysenteriae TTPHUS • TTP – More common in adults – Untreated mortality rate of 80% 1 to 3 months after diagnosis – Aggressive plasma exchange has dropped the mortality to 17% – Splenectomy, immune globulin, vincristine all play a role in therapy TTPHUS • AVOID PLATELET TRANSFUSION – May lead to additional microthrombi in circulation – Transfuse only with life threatening bleeding Dilutional Thrombocytopenia • PRBC are platelet poor • Monitor platelet count with every 10 u PRBC • Transfuse when count below 50,000 • Get them upstairs before you transfuse 10 units PRBC DIC • A few harmless snowflakes working together can create an avalanche of Destruction. DIC • Early recognition important secondary to potentially devastating sequelae and effective therapy • DIC Sequence  Platelets and coagulation factors consumed  Thrombin directly activates fibrinogen Fibrin deposition  Fibrinolysis  Inhibition of platelets and fibrin polymerization  Decrease in inhibition levels • Entire process leads to a massive consumption of coagulation factors DIC • Life threatening combination of bleeding diathesis with small vessel ischemia • There are varying levels of acuity • Recommended testing – Peripheral Smear: Low platelets, schistocytes – Platelet count: Low (<100,000) – Pt, PTT, Thrombin Time: Prolonged – Fibrinogen: Low – Fibrin degredation products: zero to large DIC • Treatment – Dependent on whether bleeding or ischemia predominate – If bleeding • Platelets, FFP or Cryoprecipitate, and blood recommended – With Ischemia • Heparin has a place in treatment • Examples include Retained fetus, purpura fulminans, giant hemangioma, and acute promyelocytic leukemia DIC • Treatment – Goal in ER is suspicion, aggressive pursuit of diagnosis, understanding complications, and rarely initiation of therapy Coagulation Pathway Defects • Hemophilia A • Von Willebrand’s Disease • Hemophilia B ( Christmas Disease) Hemophilia A Hemophilia A • • • • Variant form of Factor VIII 60 to 80 persons per million 70% Sex linked recessive Severity linked to level of VIII:C activity – 1% Severe – 1%-5% Moderate – 5-10% mild ( little risk of spontaneous bleeding) Hemophilia A • Bleeding can occur anywhere – – – – Deep muscles Joints Urinary Tract Intracranial • Recurrent Hemarthrosis and progressive join destruction are major cause of morbidity • Intracranial bleed is major cause of death in all hemophiliacs Hemophilia A • Mucosal bleeding is rare unless associated with von Willebrands or Platelet inhibition • Unlike platelet defects Trauma initiates bleeding • Bleeding can occur usually by 8 hours but as late as 1 to 3 days after trauma Hemophilia A • Management: – Home therapy is increasingly common and most report to ER only with complicated problems or Trauma – Hospitals should have files of known hemophiliacs in the area – Accepted therapy is with Factor VIII replacement or VIII:C – Newer preparation carry lower risk for Hep B and Hep C transmission Hemophilia A • Management: – Multiple guidelines for therapy institution – Most important physician should believe a patient saying they are bleeding and institute early therapy Hemophilia A • Prophylaxis – May require admission for anticipation of delayed bleeding – Candidates: • Deep lacerations • Soft tissue injury where hematoma could be destructive ie: eye, mouth, neck, back, and spinal column Hemophilia A • Treatment of haemophilic synovitis – COX-2 important in Hemophiliacs because of anti=inflammatory,and analgesic properties but they do not affect the platelet fuction – With withdrawl of rofecoxib from the market celecoxib had become popular – Study has shown that Celecoxib gives good relief of synovitis without serious adverse effects Von Willebrand’s Disease • Most common inherited bleeding disorder • Without vWF the ability of platelets to adhere is diminished • VIII:C has diminished activity • Bleeding sites are primarily mucosal • Hemarthrosis is rare • Menorrhagia and GI bleed are common Von Willebrand’s Disease • Factor VIII replacement is treatment of choice • FFP may be given in extreme circumstances • Desmopressin is only useful for specific types of vWD and should only be give with advice from hematologist Hemophilia B (Christmas Disease) Hemophilia B (Christmas Disease) • Clinically indistinguishable from hemophilia A • Deficiency of factor IX • Factor IX preparation used in treatment • FFP and plasma prothrombin complex are also useful • Gene manipulation in animals shows promising results for the future Take home message • All Bleeding stops…. Eventually References • Rosen’s • Emedicine • Celecoxib in the treatment of haemophilic synovitis, target joints, and pain in adults and children with haemophilia, Haemophilia (2006), 12, 514-517