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72 Cards in this Set
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Thrombocytopenia
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<150,000 /uL (Normal 150,000 – 350,000/uL)
Spontaneous bleeding <20,000 /uL Usually involves small vessels of skin, mucous membranes GI/GU tracts Intracranial bleeding can be serious problem too! |
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Thrombocytopenia
Causes |
- Decreased platelet production
- Bone marrow problems, e.g. aplastic anemia, MDS, vitamin deficiency, tumors - Decreased platelet survival - Immunologic, i.e. circulating anti-platelet antibodies to GpIIb/IIIa or GpIb - ITP, HIV, drugs - Mechanical destruction/consumption, e.g. MAHA, prosthetic heart valves - Sequestration - Dilutional |
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Thrombocytosis
Complications |
- THROMBOTIC episodes, due to the increased number of active platelets
- BLEEDING episodes, as platelet function may also be defective |
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Thrombocytosis
Secondary/Reactive |
Infections
Iron deficiency anemia Inflammatory disorders Acute/chronic blood loss Drugs (steroids) Malignancies (Classical Hodgkin Lymphoma) Splenectomy |
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Primary Thrombocytosis
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Essential Thrombocytosis
CML Polycythemia Vera Chronic Idiopathic Myofibrosis |
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PTT
Reference Range |
21 – 31
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PT
Reference Range |
10.8 – 13.9
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Fibrinogen
Reference Range |
180 – 363
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D-Dimer
Reference Range |
<230
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Immune Thrombocytopenic Purpura
Dx |
- Peripheral Blood: Thrombocytopenia
- Bone Marrow: Normal/increased numbers of megakaryocytes - No known exposure to thrombocytopenic agents Labs: normal PT, aPTT |
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Immune Thrombocytopenic Purpura
Acute |
children, self-limiting (acute viral infection)
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Immune Thrombocytopenic Purpura
Chronic |
adults (autoimmune syndromes, infections, drugs, HIV)
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Immune Thrombocytopenic Purpura
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- Antiplatelet antibodies to GPIIb/IIIa or GpI/IX
Coat and damage platelets, which are then selectively removed from circulation by spleen - May be secondary or primary (idiopathic) |
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Platelet Phase Tests
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- Bleeding Time (BT)
- Platelet Enumeration - Aggregation Studies |
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Bleeding Time (BT)
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- Normal: 2-9 minutes
- Non-specific, very difficult to standardize - Diagnoses: thrombocytopenia, VWD, primary hemostasis problems |
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Platelet Enumeration
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- Normal: 150-350 K
- Usually requires < 50K before bleeding occurs - Diagnoses: thrombocytopenia vs. thrombocytosis |
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Aggregation Studies
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- Addition of platelet aggregators, e.g. ADP
- Diagnoses: Platelet function defects |
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Activated Partial Thromboplastin Time (aPTT)
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Normal: 21 - 35 seconds
Diagnoses: - increased aPTT Sensitive to Intrinsic Pathway abnormalities: XII, XI, IX, VIII, X, V - Less sensitive to II, fibrinogen |
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Prothrombin Time (PT)
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Normal: 10-14 seconds
Diagnoses: - increased PT: Sensitive to Extrinsic Pathway abnormalities: VII, X, V, II, fibrinogen - Useful in Vitamin K deficiency: II, VII, X |
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Fibrinogen Degradation Products (FDPs)
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Measures presence of fibrin or fibrinogen degradation products
- Antibodies to FDPs are bound to latex particles, which clump in the presence of antigen - False positive and negatives are common - Sample procurement techniques (in vitro clotting) - Liver disease, rheumatoid arthritis - D-dimer test preferred - More specific for fibrinolysis - Normal < 200 ng/mL |
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Fibrinogen Degradation Products (FDPs)
When it is useful? |
- DIC, level usually very elevated
- DVT, post-operative, acutely ill level elevated, not as high as seen in DIC |
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If you have an:
eleveated PT elevated aPTT decreased platelets then you suspect? |
DIC
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Linitis plastica
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- 'leather-bottle' stomach
- due to poorly differentiated adenocarcinoma infiltrating gastric wall. - this type of gastric carcinoma does not ulcerate or protrude into the gastric lumen. |
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Microangiopathic hemolytic anemias (MAHA)
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Endothelial damage in microvasculature
- Disseminated intravascular coagulation - Thrombotic thrombocytopenic purpura - Hemolytic uremic syndrome |
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Mechanical/Vascular hemolysis
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Direct mechanical trauma from hemodynamic defect and/or extreme turbulence
- Prosthetic heart valves, vascular malformations - Malignant hypertension - Severe burns - “March hemoglobinuria", karate, bongo drumming |
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Reasons for RBC Fragmentation Syndromes?
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Mechanical/Vascular hemolysis
Microangiopathic hemolytic anemias |
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Disseminated Intravascular Coagulation (DIC)
(systemic activation of |
I. Coagulation system: widespread expression of tissue factor (TF)
- Intravascular THROMBUS formation (compromising blood supply to various organs) - Exhaustion of platelets and coagulation factors resulting in HEMORRHAGE. II. Fibrinolytic system: Plasmin degrades fibrinogen and fibrin, producing fibrin degradation products (FDPs), exacerbating bleeding |
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Disseminated Intravascular Coagulation (DIC)
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A secondary condition in which microthrombi develop throughout the bloodstream, blocking small blood vessels and depleting platelets and clotting factors needed to control bleeding.
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Disseminated Intravascular Coagulation (DIC)
Clinical Features |
- Bleeding is usually severe
- Petechiae and ecchymoses of skin and mucous membranes - Shock - Signs of the underlying disease are usually present - Organ(s) involved with accompanying signs/clinical effects must also be taken into consideration. |
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Disseminated Intravascular Coagulation (DIC)
Laboratory Diagnosis |
- Increase PT/aPTT
- Thrombocytopenia - Increase D-dimers (FDPs) also... - Schistocytes in blood smears - Decreased concentrations of coagulation factors V/VIII |
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Malignancies Associated w/ DIC
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solid tumors, hematologic
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Obstetric Emergencies Associated w/ DIC
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amniotic fluid embolism, abruptio placentae
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Organ Destruction Associated w/ DIC
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severe pancreatitis, severe hepatic failure
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Sepsis/Severe Infection Associated w/ DIC
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(any microorganism)
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Severe toxic or immunologic reactions Associated w/ DIC
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snake bites, recreational drugs, transfusion reactions, transplant rejection
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Vascular abnormalities associated with DIC
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Kasabach-Merritt syndrome, large vascular aneurysms
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Thrombotic Thrombocytopenic Purpura
Laboratory Dx |
- Deficiency of vWF metalloproteinase ADAMTS13
- Enzyme deficiency results in accumulation of very-high-molecular weight multimers of vWF, promoting platelet aggregation. - Acquired (antibody inhibitor) or inherited - Consumptive thrombocytopenia - Schistocytes in blood smears |
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Hemolytic Uremic Syndrome
Clinical Features |
MAHA
Thrombocytopenia Renal Insufficiency Bloody Diarrhea |
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Hemolytic Uremic Syndrome
Laboratory Dx |
- E. COLI INFECTIOUS GASTROENTERITIS
- E.coli strain 0157:H7 elaborates Shiga-like toxin absorbed by GI tract and binds to endothelial cells, initiating platelet activation - Consumptive thrombocytopenia - Schistocytes in blood smears |
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How do you get E.coli strain 0157:H7?
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eating uncooked meat...food poisoning
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aPTT mix
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to rule out possible coag inhibitor substances in blood, e.g. heparin
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TT
(Thrombin Time) |
- thrombin time measures activity of thrombin in the conversion of fibrinogen into fibrin by thrombin. Useful for diagnosis of dysfibrinogenemia
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vWF Ag
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- vonWillebrand Factor Antigen measures the serum level of vWF
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If you are still clinically concerned about a bleeding disorder but your baseline bleeding tests look fine, then what do you order?
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- aPPT mix
- Factor VIII - Factor IX - Thrombin Time - vWF Ag |
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Von Willebrand’s Factor
Functions |
- CARRIER PROTEIN FOR VIII Stabilizes VIII, increasing serum half life
- BINDS TO GpIb RECEPTOR on platelets adhesion to damaged endothelium |
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Von Willebrand’s Factor
Endothelium Pro-thrombotic properties |
- Endothelial production of von Willebrand Factor (vWF)
- Synthesis of Tissue Factor, activating extrinsic cascade |
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Von Willebrand’s Disease
Mild Forms |
TYPE1, TYPE 2
- Many patients asymptomatic - Cutaneous/mucosal bleeding: epistaxis, ecchymoses, menorrhagia, GI |
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Von Willebrand’s Disease
Severe Forms |
TYPE 3
- Usually with concomitant low levels of Factor VIII - Severe bleeding: Hemarthroses, dissecting hematomas |
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Von Willebrand’s Disease
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Bleeding Disorder
- Characterized by mucocutaneous bleeding episodes - Most common bleeding disorder - 1% of general population - Autosomal Dominant or Recessive - Multiple genetic mutations - Results in either a quantitative or qualitative deficiency of vWF |
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Von Willebrand’s Disease
Diagnostic Approach |
- Hematologic evaluation of peripheral blood
- Screening for hemostasis - I.e. platelet count, PT, aPTT, etc. - vWD panel - Factor VIII activity – decreased in vWD - vWF antigen – decreased in vWD - Ristocetin cofactor activity – decreased in vWD - vWF multimeric analysis – qualitative test of vWF |
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How is vWF secreted?
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in multimers of themselves
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Multimeric Analysis of vWF
Type 1 |
- generalized decrease in all sizes of multimers
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Multimeric Analysis of vWF
Type 2 |
- loss of high molecular weight multimers
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Multimeric Analysis of vWF
Type 3 |
multimer absence
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Hemophilia A
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- 2nd most common inherited coagulation disorder, 1:5,000 male births
- Sex-Linked (X-Linked) Recessive - Xq28 - Sporadic gene mutations very common - 30% cases with negative family history - Spectrum of bleeding manifestations - Recurrent hemarthroses, severe hemorrhagic diathesis - Exsanguinating hemorrhage from trivial trauma - Deep muscle (psoas)/joint hematomas, easy bruising, post-surgical oozing |
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Suspect Hemophilia A if
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1. . Birth of infant to mom with family history
2. Appearance of bleeding in neonatal period 3. Pattern of bleeding (joint/muscle), easy bruising |
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Factor VIII
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- Synthesized in liver
- Circulates bound to von Willebrand Factor as stable complex - Activated by IIa (and Xa!): Enhances activation of X by IX 200,000 fold - Inactivated by Protein C |
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Factor IX
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Plasma thromboplastin, Christmas factor
- Vitamin K dependent - Activated by XIa and VIIa |
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Hemophilia B
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- X-linked recessive, 1:30,000 male
- Most families have unique mutation - Spectrum of bleeding manifestations - Exsanguinating hemorrhage from trivial trauma - Deep muscle (psoas)/joint hematomas, easy bruising, post-surgical oozing Acquired - Liver disease, vitamin K deficiency - Warfarin/coumadin therapy |
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Hemophilia B
Therapy |
Administration of Factor IX
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Liver Disease
as an Acquired Coagulopathy |
- Hepatitis/Cirrhosis
- Major site of clotting factor synthesis: all factors but vWF - Usually results in bleeding diathesis |
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Vitamin K Deficiency
as an Acquired Coagulopathy |
- Biliary obstruction, malabsorption syndromes, nutritional deficiencies, drugs (affecting gut flora)
- Vitamin K-dependent factors: II, VII, IX, X, Proteins C/S - Results in bleeding diathesis |
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Disseminated Intravascular Coagulopathy
as an Acquired Coagulopathy |
- Tissue Factor expression - cancers, tissue injury, burns, infections, toxins, drugs
- Uncontrolled generation of thrombin/microthrombi - “consumes” platelets/factors - Subsequent thrombolysis adds to bleeding tendency - increase fibrin split products - Usually results in purpuric manifestations |
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Westermark sign
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Pulmonary Angiogram Sign
Dilatation of pulmonary vessels proximal to embolism along with collapse of distal vessels, often with a sharp cut off. |
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APC Mix
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PTT performed in the presence and absence of exogenously supplied activated protein (APC). In normal patients, the APC degrades the patient's factor Va and VIlla, and on that basis, prolongs the PTT. In patients with a factor V Leiden mutation, the degradation of factor Va does not occur to the same extent and, therefore, the PTT does not become as prolonged. The ratio of the PTT + APC versus PTT without is calculated. Normal individuals typically have ratio of 2.0 or greater, and individuals with factor V Leiden typically had a ratio less than 2.0.
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Factor V Leiden
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Most common inherited thrombotic disorder
- Accounts for 20-50% of thrombotic disorders - Autosomal Dominant, point substitution mutation at nucleotide 1691 resulting in Arg506 --> Gln - MUTATION IN Factor V RENDERS THE COFACTOR RESISTANT TO PROTEOLYSIS BY ACTIVATED PROTEIN C - Recurrent venous thromboembolism, may be asymptomatic |
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Factor V Leiden
Dx |
DNA mutational Analysis
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Factor V Leiden
Treatment |
prophylaxis anticoagulation (warfarin)
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Hypercoagulability
Primary Genetic |
(see venous thrombi)
- Mutation in Factor V gene - Mutation in Prothrombin gene 20210A - Antithrombin III, protein C/S deficiencies - Fibrinolysis defects |
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Antiphospholipid Antibody Syndrome
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Prothrombotic disorder
- Autoantibodies directed against a number of antigens complexed to phospholipids - Autoimmune syndromes - Lupus anticoagulant, anticardiolipin antibody - Direct platelet activation, interference of protein C activity - Recurrent venous and arterial thromboembolism, fetal loss (multiple spontaneous abortions), thrombocytopenia, variety of neurological manifestations - Most often diagnosed because of incidental paradoxical elevated aPTT - In vitro artifact caused by interaction of the antibodies with the phospholipid reagant used in the test assay |
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List the Hereditary Thrombophilias
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- Factor V Leiden
- Prothrombin 20210A transition - Methylene tetrahydrofolate reductase mutation (MTHFR C6771T) - Protein C/S deficiencies - Antithrombin deficiency |
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Thrombophilic Disorders
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- Hereditary Thrombophilias
- Antiphospholipid Antibody Syndrome - Disseminated Intravascular Coagulation (DIC) - Heparin-induced Thrombocytopenia syndrome (HIT). |