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102 Cards in this Set
- Front
- Back
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Formation of a Platelet Plug
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Primary Hemostasis
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Activation of the Coagulation Cascade
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Secondary Hemostasis
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Platelets are activated by exposure to what three things?
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thrombin, collagen and clot mediators from damaged epithelium
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This allows for platelets to adhere to the epithelium?
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VWF
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Attached platelets release what four main things?
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Fibrinogen, Platelet Factor-IV, Clotting Factor V, Platelet-Derived Growth Factor
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These on the platelet surface activate the intrinsic clotting pathway
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Negatively charged phospholipids
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This supplies fibrin threads around the platelet
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Clotting Factor V
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This contracts & pulls platelets into a tight plug
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Platelet actinomycin
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Stimulated by thrombin & negatively charged collagen released from the damaged epithelium or by negatively charged phospholipids on the surface of platelets to activate Factor XII
Factors XII, XI, IX, VIII |
Intrinsic pathway of Secondary Hemostasis
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Tissue Factor released by damaged epithelium activates Factor VII
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Extrinsic pathway of Secondary Hemostasis
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Factors X, V, II,I, XIII
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Common Pathway of Secondary Hemostasis
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Inhibits Factors II, IX, X, XI, XII
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Antithrombin III
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Inhibits Factors V, VIII
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Proteins C & S
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Inhibits Factor X
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Tissue Factor Pathway Inhibitor (TFPI)
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These cause vasodilation & inhibit platelet activation
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Prostacyclin and Nitrous Oxide (NO)
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This inhibits platelet attraction & aggregation
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Ecto-ADPase
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Endothelial cells generate?
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endogenous Heparin
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Endothelial cells generate endogenous Heparin which in turn?
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Increases activity of antithrombin III inhibiting Factors II, IX, X, XI, XII
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Assesses extrinsic & common pathways
Used to Monitor Warfarin (Coumadin) Therapy |
Prothrombin Time (PT): Nml 11-16 seconds
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Used to standardized variations amongst PT results
INR: Patient PT divided by Control PT |
International Normalized Ration (INR)
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Causes of a Prolonged PT/INR?
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Factor Deficiencies ( I, II, V, VII, X), Vitamin K Deficiency, Chronic Liver Disease, DIC
Warfarin Therapy |
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Assesses the intrinsic and common pathways
Used to monitor Heparin |
Activate Partial Thromboplastin Time (aPTT): 33-45 seconds
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Causes of Prolonged aPTT?
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Factor Deficiencies: I, II, V, VIII, IX, X, XI & XII, Liver Disease, Vitamin K Deficiency, DIC, Antiphospholipid Antibodies
Heparin Therapy |
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Evaluates platelet function and quantity, and vascular constriction ability
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Bleeding Time: Nml 3-8 minutes
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Causes of a Prolonged Bleeding Time?
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Bone Marrow Failure, Thrombocytopenia, Leukemia, von Willebrand Disease, DIC, Liver Disease
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What is the differential mnemonic for bleeding disorders
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CALF DIPS
Cirrhosis Aspirin Leukemia Factor VIII, IX, XI Dysfunction Disseminated Intravascular Coagulation (DIC) Immune Thrombocytopenic Purpura (ITP) Platelet Deficiency Scurvy |
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Vitamin K dependent clotting factors (II, VII, IX & X) & fibrinogen are made in the liver
Prolonged PT, aPTT, elevated direct bilirubin Treat with Fresh Frozen Plasma |
Cirrhosis (Liver Disease)
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ASA decreases platelet aggregation for the life of the platelet
NSAIDS reversibly decreases platelet aggregation |
Aspirin (NSAIDS)
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Bone marrow invasion of malignant cells produces thrombocytopenia
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Leukemia
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Coagulation Factor VIII Deficiency
X-linked Recessive Disorder Males Affected males are symptomatic 1 in 5,000 males are affected Females Are predominantly asymptomatic carriers |
Hemophilia A
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The bleeding tendency in hemophilia A is related to?
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factor VIII:C deficiency
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These are most characteristic of Hemophilia
Most common joints affected: knees, ankles, elbows, shoulder, hips |
Spontaneous hemarthroses
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Apart from spontaneous hemarthroses, these five things can be seen with hemophilia A?
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Bleeding into muscles
Intracranial Bleeding GI Bleeding Hematuria Oropharyngeal Bleeding |
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What are the laboratory findings in hemophilia A?
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aPTT is prolonged
Factor VIII levels are decreased PT normal vWF normal |
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Plasma from a hemophiliac patient mixed with normal plasma will?
Failure to normalize indicates the presence of? |
1. normalize the aPTT
2. Factor VIII inhibitor |
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What is involved with transfusion therapy of hemophilia A?
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Factor VIII Concentrate
Half-life is approximately 12 hours so it is given twice day |
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What is involved with non-transfusion therapy of hemophilia A?
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DDAVP
Vasopressin analogue which causes a transient rise in Factor VIII EACA (Amicar) Used to manage bleeding after DDAVP or infusion therapy |
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Formation of antibodies to Factor VIIII which neutralize Factor VIII clotting activity
Can have spontaneous or acquired inhibitors About 15% of patients who receive transfusions develop inhibitors to Factor VIII Attempt to eradicate the Inhibitor Immune Tolerance Induction Repeated exposure to low levels of the protein With acute bleeds, remove the antibody with plasma exchange combined with infusion of high doses of Factor VIII |
Factor VIII Inhibitors in Hemophilia A
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In control of acute bleeding in a hemophilia A patient who has low inhibitors what do you do?
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Give high doses of human or porcine Factor VIII to overcome the action of the inhibitors
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In control of acute bleeding in a hemophilia A patient who has high inhibitors what do you do?
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Treated with concentrates enriched with prothrombin, Factor VII, Factor IX, Factor X
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About 15% of patients who receive transfusions develop ?
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inhibitors to Factor VIII
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Avoid use of this product in hemophilia A patients?
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aspirin or aspirin-based products in patients with Hemophilia
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Caused by a Deficiency of Coagulation Factor IX
One in 25,000 males affected Genetically and Clinically identical to Hemophilia A X-linked Recessive Disorder Bleeding tendency and classification is related to factor IX deficiency Bleeding sites are the same Inhibitors may also be present (5%) |
Hemophilia B - Christmas Disease
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What are the laboratory findings in hemophilia B?
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Prolonged aPTT, Decreased Factor IX levels
Normal Factor VIII, and vWF |
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What is the TX of hemophilia B?
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Infusion of Factor IX Concentrates
Half-life of 18 hours Factor IX concentrate contain other proteins that activate coagulating factors Increase risk of thrombosis with high dose replacement |
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A rare autosomal recessive disorder
Affects 1 in one million Most common amongst Ashkenazi and Iraqi Jews Patients with Factor XI levels <10% of normal have high risk of bleeding Considered a mild bleeding disorder: bruising, gum bleeding, epistaxis, hematuria, menorrhagia, post-operative bleeding (most common) |
Hemophilia C Factor XI Deficiency
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What are the laboratory findings with hemophilia C?
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Prolonged aPTT, Decreased Factor XI
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What is the TX of hemophilia C?
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Fresh Frozen Plasma with Factor XI Concentrate
Factor XI half-like is approximately 40-70 hours so it is given every other day when needed |
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Risk factors for this include underlying illnesses:
Sepsis Severe Tissue Injury (Burns) Obstetric Complications (Abruptio Placentae) Surgical Complications Cancers Hemolytic Transfusion Reactions Snake Bites |
DIC - DISSEMINATED INTRAVASCULAR COAGULATION
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Due to overwhelmingly high levels of circulating THROMBIN
Stimulated by tissue factors & causes simultaneous suppression of physiologic anticoagulants (Protein C) Thrombin changes fibrinogen to fibrin, stimulates platelet aggregation, activates Factor V & VIII & releases plasminogen activator which cleaves to plasmin Plasmin cleaves fibrin causing Fibrin Degradation Products (D-Dimer) and continues to stimulate Factors V & VIII Sustained elevation of the coagulation cycle results in consumption of clotting factors, fibrinogen & platelets and further bleeding |
DIC
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DIC - Excess thrombin produces what four things?
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Hypofibrinogenemia
Thrombocytopenia Depletion of Coagulation Factors Fibrinolysis |
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DIC - Clinical manifestations include both?
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bleeding and thrombosis
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Bleeding from any body site
Most commonly visible as bleeding or oozing at venipuncture site and wounds Petechiae, Ecchymosis |
Bleeding associated with DIC
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Most common as digital ischemia & gangrene
Microcirculation vessel occlusion leading to end organ damage |
Thrombosis associated with DIC
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What are the six laboratory findings with DIC?
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Thrombocytopenia
Prolonged PT & aPTT Hypofibrinogenemia Elevated Fibrin Degradation Products (D-Dimer) Increased Liver Functions Hemolytic Anemia |
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Manifested as recurrent superficial and deep venous thrombosis (Trousseau’s Syndrome)
Elevated D-Dimer |
Subacute DIC in cancer patients
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What is the TX for DIC?
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Primary order is to treat the underlying cause of DIC
Fresh Frozen Plasma may be given to replace coagulation factors Fibrinogen replacement is with cryoprecipitate Platelets may be needed EACA (Amicar) can be given to decrease rate of fibrinolysis, increase fibrinogen levels & to control bleeding May have to be used with Heparin to prevent thrombosis |
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DIC - This is indicated when there is evidence of thrombosis or fibrin deposition leading to acral cyanosis
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Heparin
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Bone Marrow Infiltration, Marrow Hypoplasia due to Radiation Exposure, Heparin Induced Thrombocytopenia, Alcohol Abuse, Megaloblastic Anemia (Vitamin B12 Deficiency)
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Platelet dysfunction - decreased production
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Hypersplenism, DIC, Thrombotic Thrombocytopenic Purpura (TTP), HELLP Syndrome (Hemolysis, Increased Liver Enzymes, Low Platelets)
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Platelet dysfunction - increased destruction
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Results in decreased platelet adhesion & decreased Factor VIII availability
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Platelet dysfunction - vWF dysfunction
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Vitamin C needed for collagen synthesis
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Scurvy
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What are the Vitamin K dependent coagulation factors?
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Vitamin K dependent coagulation factors:
II, VII, IX, X |
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is a cofactor for carboxylation of the gamma carbon of the glutamic acid residues in Vitamin K dependent factors
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Vitamin K
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With carboxylation, these are able to bind to platelets
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With carboxylation, the Vitamin K dependent factors are able to bind to platelets
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What are sources of Vitamin K
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Diet rich in leafy vegetables
Endogenous production by intestinal bacteria |
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What are the risk factors for Vitamin K deficiency?
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Poor diet, malabsorption, broad-spectrum antibiotic use that suppresses intestinal bacteria
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Bleeding may occur from any site
Laboratory Findings Prolonged PT > aPTT Decrease levels of Vitamin K dependent factors (II, VII, IX, X) Differential Other causes of a Prolonged PT, aPTT |
Vitamin K deficiency
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How do you treat Vitamin K deficiency?
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Quickly reversible with Vitamin K
Educate patients on diet Watch use of broad spectrum antibiotics in susceptible patients |
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What are the diagnostic studies used when trying to diagnose a bleeding disorder?
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CBC with Peripheral Smear
Nml 150,000-450,000 Chemistry Panel Vitamin B12 Level Urinalysis PT, INR, aPTT Bleeding Time Platelet Function Analysis Screens for platelet dysfunction Clotting Factor Levels Mixing Study Fibrinogen Level Nml 100-300mg/dL |
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Stasis of Blood Flow
Increase Pro-clotting Components and/or Lack of Anti-clotting Factors Endothelial (Vascular Wall) Damage |
Virchow’s Triad of a Hypercoagulable State
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Marked proliferation of megakaryocytes in the bone marrow
May be associated with JAK2 mutation Median age of presentation is 50-60 ages Increased incidence in women More commonly identified as incidental finding on labs versus thrombotic event Consider when venous thrombosis occurs in unusual places Bleeding may also occur due to platelet defect Splenomegaly may be present |
ESSENTIAL THROMBOCYTOSIS
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What is associated with the laboratory findings of essential thrombocytopenia?
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Laboratory Evaluation
Elevated Platelets Hematocrit usually normal Peripheral Smear shows large platelets Bone Marrow demonstrates increased megakaryocytes |
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What is the treatment and prognosis of essential thrombosis?
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Treatment and Prognosis
Keep platelet <500,000 Hydroxyurea is treatment of choice Anagrelide is considered 2nd line Low dose ASA daily Major cause of morbidity is thrombosis 1-5% risk of transformation to acute leukemia over 20 year period |
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Blood viscosity, fibrinogen & Factor VIII increased during pregnancy
During delivery, circulating tissue factor is increased The risk of venous thromboembolism is about 6 times higher in pregnant women |
Pregnancy and Postpartum as a hypercoagulable state.
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Causes increased prothrombin levels and a 3-fold increase risk of thrombosis
Prevalence in healthy people is about 2.3% |
Prothrombin 20210 Mutation as a hypercoagulable state.
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Occurs in 1 per 200-300 persons
Associated with DVT, superficial phlebitis |
Protein C Deficiency (More Benign) as a hypercoagulable state.
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Occurs in approximately 1 per 500 persons
Results in superficial thrombophlebitis, DVT, & PE |
Protein S Deficiency as a hypercoagulable state.
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Genetic mutation causes excessive RBC sensitivity to complement
Results in Hemolytic Anemia, Thromboses and Pancytopenia Hemolysis causes dark colored urine Clotting usually occurs in intra-abdominal organs and in the cerebral circulation |
Paroxysmal Nocturnal Hemoglobinuria as a hypercoagulable state.
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Increased bone marrow production of RBCs & platelets
Can caused increased blood viscosity, associated with thromboembolism |
Polycythemia vera as a hypercoagulable state.
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Causes endothelial cell damage, platelet adhesion
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Smoking
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Heparin associated antibodies form approximately 1 week after therapy, also increases production of tissue factor
Occurs in 1-3% of patients treated with Unfractionated Heparin Less frequent in patients taking LMWH Characterized by a 50% decrease in the platelet count four to fourteen days after exposure Associated with arterial and venous thromboses (DVT, PE) Diagnosis confirmed by + FP4-Heparin Antibody Assay Discontinue the Heparin and administer a Direct Thrombin Inhibitor: Argatroban, Lepirudin |
Heparin-Induced Thrombocytopenia
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Deficiencies in Vitamins B12, B6 & Folic Acid will lead to elevated levels of homocysteine
Homocysteine is metabolized to methionine and cysteine which requires Folic Acid, Vitamin B12 & Vitamin B6 May also be caused by genetic lack of the enzyme that breaks down homocysteine Hyperhomocysteinemia causes direct damage to blood vessels, accelerates atherosclerosis and increases the risk for a thrombotic state |
Hyperhomocystemia
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Occurs in 1 per 5000 persons
Deficiency of AT III promotes the reactions of the coagulation cascade Family history of thrombosis should prompt screening as well as personal history of repetitive DVT or PE |
Antithrombin III deficiency
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Occurs in about 0.8% of patients with thromboses
Caused by excess thrombin and decreased fibrinolytic activity Associated with arterial and venous clotting |
dysfibrinogenemia
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Causes vascular endothelial damage, reduced NO, increased blood viscosity, increased vWF and increased fibrinogen
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Congestive heart failure
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High titers of antiphospholipid antibodies are associated with increased thrombosis due to increased circulating tissue factor and thrombin, decreased fibrinolysis and decreased Protein C
Associated with elevated Lupus Anticoagulant and Anticardiolipin Antibodies Manifestations include DVT, PE, repetitive miscarriages, hemolytic anemia |
Antiphospholipid syndrome
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Chronic Renal Failure associated with endothelial dysfunction, decreased NO
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Uremia
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These type of surgeries carry the highest risk of thrombosis?
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Orthopedic
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Risk of thrombosis is increased in women on HT
Estrogen increases levels of clotting factors, decreases anticoagulant levels of Protein S & Antithrombin III |
Estrogen use as a hypercoagulable state.
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Reduced insulin decreases endothelial NO production, increasing platelet activation
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Diabetes
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This can interact with platelets, endothelial cells and can activate clotting factors
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cancer cells
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Most common hereditary cause of a hypercoagulable state
Approximately 5% of whites are heterozygous for this mutation The mutation blocks the anticoagulant effects of activated Protein C on Factor V |
Leiden Factor V Mutation
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Lipoproteins can activate platelets and the clotting cascade
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Obesity and Elevated Cholesterol Levels
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Immobility due to this may lead to blood stasis?
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Trauma
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Subclinical Hyperthyroidism causes increased circulating clotting Factor V
Hypothyroidism can cause increased fibrinogen, Factor VII, decreased Antithrombin III |
Thyroid disease
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Increased platelet activation & thrombin generation
Decreased NO, Proteins C & S |
Thalassemia & Sickle Cell Disease
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Increased tissue factor from damaged endothelium activating the extrinsic clotting system
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Sepsis
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LABORATORY EVALUATION FOR HYPERCOAGULABLE DISORDERS?
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CBC with Peripheral Smear
Chemistry Panel Urinalysis TSH Lipid Profile PT, INR, aPTT D-Dimer Hypercoagulable Panel Protein C & S Antithrombin III Assay Leiden Factor V Prothrombin 20210 Homocysteine Level Anticardiolipin ANA Antiphospholipid Antibodies Lupus Anticoagulant Fibrinogen Level HIT Assay |
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How do you decrease risk factors for clotting?
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Decrease Smoking
Weight Reduction Decrease Immobility |
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What underlying illnesses do you need to manage in order to avoid clotting problems?
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Lipids
DM Heart Failure Renal Disease PV Sickle Cell, Thalessemia Thyroid Disease |
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What antiplatelet can you use to avoid clotting?
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Aspirin or NSAIDs
Clopidogrel (Plavex) Prevents platelet activation May combine with ASA Contraindicated in patients with allergy to ASA Dipyridamole (Persantine) Used in patients with cardiac valve replacement Can be combined with ASA Abciximab (ReoPro), Tirofiban (Aggrastat), Eptifibatide (Integrilin) Block IIb-IIIa glycoprotein receptors on platelet surface Prevent platelet to platelet binding Uses in patients with acute MI |
