Presentation on theme: "Coagulopathies Hayley Morse May 29, 2008. Normal Hemostasis First, injury to a blood vessel leads to immediate vasoconstriction, as well as activating."— Presentation transcript:
Coagulopathies Hayley Morse May 29, 2008
Normal Hemostasis First, injury to a blood vessel leads to immediate vasoconstriction, as well as activating the coagulation cascade. Platelet adhesion: results from exposure of blood to subendothelial collagen Adhesive proteins (von Willebrand factor and fibrinogen) mediate the adhesion of platelets to the subendothelium Primary hemostatic plug is formed after platelets aggregate. Platelet plug is unstable and short-lived, but serves as a framework for secondary hemostasis.
Normal Hemostasis Activation of intrinsic pathway (contact phase) results in fibrin formation This process occurs almost simultaneously with platelet adhesion and aggregation
Intrinsic Pathway Factor XII is activated by contact with subendothelial collagen and the platelet plug Prekallikrein and high molecular weight kininogen are important cofactors for factor XII activation Fibrin (secondary hemostatic plug) is the result (through the Common Pathway) The secondary hemostatic plug is stable and long-lasting.
Extrinsic Pathway Tissue factor (factor III) is released whenever there is tissue trauma, and this activates the extrinsic pathway End result is also fibrin formation through the Common Pathway
Nomenclature of clotting factors I – fibrinogen II – Prothrombin III – Tissue thromboplastin/tissue factor IV – Calcium V – Proacelerin VII – Proconvertin VIII – Hemophilia A (antihemophilic factor) IX – Hemophilia B (Christmas factor) X – Stuart-Prower factor XI – Plasma thromboplastin antecedent (PTA) XII – Hageman factor XIII – Fibrin stabilizing factor Prekallikrein/Fletcher factor High molecular weight kininogen (HMWK)/Fitzgerald factor
Fibrinolysis Fibrinolysis prevents excessive thrombus (clot) formation It is activated by stimuli that activate the Intrinsic pathway (exposure to subendothelial collagen and the platelet plug) Plasminogen is activated and becomes Plasmin, which is responsible for lysis of a clot; as well as inhibition of platelet aggregation and activation of clotting factors in the affected area
Natural anticoagulants Other natural anticoagulants are activated by initiation of coagulation cascade (Antithrombin and proteins C and S). Antithrombin is a protein synthesized by hepatocytes, and inhibits the activation of factors IX, X, and thrombin Acts as a cofactor for heparin Proteins C and S are also produced by hepatocytes, and are Vitamin K-dependent
Important questions to ask owners when animal presents with spontaneous or excessive bleeding: Is this the first bleeding episode? Has the pet had any surgeries before this, and if so, did the pet bleed excessively? Do any littermates have similar clinical signs? Was there increased perinatal mortality in the litter? Has the pet recently been vaccinated (especially with modified-live vaccines)? Is the pet receiving any medications? Does the pet have access to rodenticides or does it roam freely?
Clinical signs association with disorder of primary hemostasis Petechiae, ecchymoses common on mucous membranes and skin Bleeding from mucosal surfaces (epistaxis, gingival bleeding, hematuria, melena, hematochezia, hyphema) Prolonged bleeding after venipuncture
Clinical Signs associated with disorder of secondary hemostasis Hematomas are common Bleeding into muscles, joints, and body cavities (i.e. hemoabdomen, hemothorax) Delayed bleeding after venipunture
Coagulation tests Evaluation of blood smear – Platelet number – Platelet morphology Look for platelet clumps and estimate platelet number General rule: # platelets/oil x 15,000 = estimated platelet count (plts/ul) Schizocytes (fragmented rbcs) suggest microangiopathic hemolysis (DIC)
Coagulation Tests Buccal mucosa bleeding time (BMBT): time in minutes for bleeding to cease from a standardized incision (laceration in upper lip) Evaluates formation of platelet plug and depends upon: – Adequate number of platelets – Adequate function of platelets – Normal blood vessel wall structure
Coagulation Tests Activated partial thromboplastin time (APTT): time in seconds for clot formation in citrated plasma after addition of contact activator, phospholipid, and calcium Platelets have no effect on this test since phospholipid is added Evaluates intrinsic and common pathways Detects 30% or less factor activity in these pathways
Coagulation tests One-stage prothrombin test (OSPT or PT): time in seconds for clot formation in citrated plasma after addition or thromboplastin and calcium Platelets have no effect on test since adding tissue thromboplastin (factor III) Factor VII has the shortest half-life Evaluates Extrinsic and Common Pathways Detects 30% or less factor activity
Coagulation tests Thrombin clotting time (TCT): time in seconds for clot formation in citrated plasma after addition of thrombin and calcium Most sensitive measure of fibrinogen concentration Prolonged TCT with: – Hypofibrinogenemia (DIC) – Increased FDPs, D-dimers – Heparin treatment – Uremia
Coagulation tests Fibrin degradation products (FDPs): formed when plasmin dissolves the fibrin clot Ultimately are removed by the liver (half-life 9-12 hours).
Coagulation tests D-dimers: unique FDPs that are formed when cross-linked fibrin is lysed by plasmin Specific for active coagulation and fibrinolysis D-dimer is a sensitive test for DIC and likely is superior to traditional FDP assays for this purpose
Disorders of Primary Hemostasis In theory, spontaneous bleeding as a result of primary hemostatic defect could be due to one of three mechanisms – Thrombocytopenia (decrease platelet number) – Thrombopathia (platelet dysfunction) – Vascular defect Thrombocytopenia is most common cause; others are rare.
Decreased platelet production Most common cause for thrombocytopenia in cats Usually caused by retrovirus-induced bone marrow disorders (FeLV) Other causes: Drugs (estrogen, phenybutazone, some chemo agents); toxins; radiation; infectious (FIV); neoplastic process in bone marrow; specific platelet infectious agents (Ehrlichia platys); pure megakaryocytic hypoplasia (rare) Diagnosis by bone marrow aspiration or biopsy
Increased platelet destruction Most common cause of thrombocytopenia in dogs; extremely rare in cats Immune-mediated: – Primary: Idiopathic, Evan syndrome, systemic lupus erythematosus – Secondary: Drugs, live-virus or modified-live virus vaccination, tick-borne disease, neoplasia, bacterial infection
Increased platelet consumption Occurs most commonly in dogs and cats with DIC Other causes: Acute Hemorrhage, Neoplasia, Microangiopathies, Sepsis, vasculitis, splenic torsion, hyperslenism, hepatic disease, hemolytic uremia syndrome
Platelet dysfunction Can be congenital (von Willebrands disease) or acquired – more common Rarely result in spontaneous bleeding Acquired causes - secondary to: – Drug therapy (esp. aspirin, cephalosporins, B-lactams, synthetic colloids) – Uremia – Neoplasia – DIC – Monoclonal gammopathies (multiple myeloma, plasma cell ) – Ehrlichiosis – Retroviral infections – Snake venom
Von Willebrands disease More common in dogs; rare in cats Common in Doberman pinschers, GSD, Poodles, Golden retrievers, Shetland sheepdogs. vWF is produced by megakaryocytes and endothelial cells, and it circulates in plasma complexed to factor VIII It is important in the formation of the primary platelet plug (causes platelets to adhere to subendothelial cartilage)
vWD Usually see excessive bleeding during or after surgery Excessive bleeding during teething and estrus can occur Perinatal mortality or abortion/stillbirths are common in litters with vWD BMBT is most cost effective screening test in at- risk breeds Can also send out blood to quantify vWF: <50% indicate vWF deficiency
Treatment of vWD Fresh frozen plasma, whole fresh blood, or cryoprecipitate - causes the circulating vWF concentration to increase within minutes Desmopressin acetate – causes massive release of vWF from endothelial cells Can use topical hemostatic agents (fibrin, collagen, methacrylate) to control local bleeding
Disorders of secondary hemostasis: Congenital Specific factor deficiencies Clinical severity depends on magnitude of factor deficiency and the exposure of the animal to trauma that may cause bleeding. Most animals develop bleeding in the first year of life. Mildly affected animals may not bleed until later in life, especially if they do not undergo surgery or trauma.
Inherited Coagulopathies Should be suspected in younger animals, esp taking breed into account Should be suspected if there is a history of recurrent bleeding If acquired causes have been ruled out Diagnosis requires specific factor assays performed by specialized laboratories.
Inherited Coagulopathies Treatment is aimed at controlling bleeding If bleeding is severe, transfusion of plasma products is indicated to provide needed clotting factor(s). For deficiencies of factors VIII and I, cryoprecipitate is the ideal plasma product. For deficiencies of factors II, VII, IX, X, and XI, cryosupernatant is ideal. Fresh frozen plasma is an acceptable alternative.
Disorders of Secondary Hemostasis: Acquired Vitamin K deficiency and antagonism Hepatic disease DIC
Vitamin K deficiency Synthesis of Vitamin K-dependent factors occurs in the liver Factors II, VII, IX, X Vitamin K is an essential cofactor (for carboxylation) to activate these factors Anticoagulant rodenticides interfere with recycling of Vitamin K, resulting in rapid depletion Proteins C and S are also vitamin K-dependent
Diagnosis Factor VII has shortest half-life (4-6 hours), so will see prolongation in PT first Clinical signs usually occur 2-3 days after ingestion By the time hemorrhage is seen, PT and APTT will be prolonged FDP, D-dimer, and fibrinogen concentrations are usually normal Platelet count is usually normal, but can be decreased due to consumption
Treatment Fresh frozen plasma or whole fresh blood to replenish clotting factors Prbc transfusion if animal is anemic Vitamin K1 – 5mg/kg SC in multiple sites, followed by oral Vitamin K1 2.5mg/kg BID 12 hrs later (give with fatty meal to enhance absorption) May take 12 hours to shorten PT
Hepatic Disease Severe damage to hepatocytes or obstruction of bile duct results in variable factor deficiencies and/or abnormalities in Vitamin K metabolism Disorders of platelet number and function may occur PT and PTT can be prolonged FDP, D-dimer, and fibrinogen concentrations may be increased due to reduced clearance of plasminogen activators, as well as reduced synthesis of fibrinolytic inhibitors
Hepatic Disease Based on results of coagulation tests, may be difficult to differentiate from DIC Look to physical exam findings, chemistry profile changes, and liver function testing. Treatment with fresh frozen plasma transfusion +/- Vitamin K1 Repeat coags in 12 hrs to assess if Vitamin K1 was beneficial
Disseminated Intravascular Coagulation Excessive intravascular coagulation leads to multiple organ microthrombosis. Multiple organ failure (MOF) or multiple organ dysfunction syndrome (MODS) can be a consequence. Paradoxical bleeding occurs due to the inactivation or excessive consumption of platelets and clotting factors secondary to enhanced fibrinolysis. DIC is a complex syndrome, and is a common pathway in a variety of disorders
DIC General mechanisms leading to activation of intravascular coagulation: – Endothelial damage – Platelet activation – Release of tissue procoagulants
DIC Pathogenesis First, primary and secondary hemostatic plugs form in multiple small vessels simultaneously, forming multiple thrombi in the microcirculation Ischemia is the result, leading to MOF or MODS Platelets are consumed in large numbers, leading to thrombocytopenia
DIC Pathogenesis Second, fibrinolytic system is activated, and this results in clot lysis and the inactivation of clotting factors and impaired platelet function. Third, antithrombin and possibly proteins C and S are consumed in an effort to stop intravascular coagulation. This effectively depletes these anticoagulants. Fourth, fibrin formation in the microvasculature causes shearing of rbcs (schistocytes), and leads to hemolytic anemia.
DIC Excessive intravascular coagulation and depletion of natural anticoagulants leads to spontaneous bleeding as a result of: – Thrombocytopenia – Impaired platelet function – Inactivation of clotting factors
DIC: Clinical signs Chronic, clinically silent form No spontaneous bleeding Abnormalities seen on blood work points to DIC Common with malignancy and possibly other chronic disorders Present for evaluation of primary problem Acute, fulminant form After heat stroke, electrocution, acute pancreatitis Or, acute decompensation of chronic, silent form (i.e. HSA) Profuse, spontaneous bleeding, plus signs secondary to anemia and MOF Both primary and secondary bleeding Extremely rare in cats
Diagnosis Hemostatic abnormalities Thrombocytopenia, prolonged PT and APTT, normal or low fibrinogen concentration, positive FDP and/or D-dimer test, decreased antithrombin concentration CBC/Chem/UA Regenerative hemolytic anemia, or nonregenerative anemia Hemoglobinemia, Schnistocytes Thrombocytopenia, neutrophilia with left shift, or rarely neutropenia Hyperbilirubinemia, azotemia and hyperphosphatemia, increased liver enzymes, decreased TCO2, panhypoproteinemia Hemoglobinuria and bilirubinuria
Treatment Stopping intravascular coagulation Maintaining good organ perfusion Preventing secondary complications Grave prognosis – Negative prognostic indicators are marked prolongation of APTT and severe thrombocytopenia – Prognosis depends on how many abnormalities are identified on coagulation tests
Thrombosis/Thromboembolism Causes – Stasis of blood – Activation of IV coagulation in an area of damaged or abnormal endothelium – Decreased activity of natural anticoagulants – Decreased or impaired fibrinolysis