week 10- heme Flashcards
What are the d/os of thrombocytopenia and platelet dysfunction?
o Acquired platelet dysfunction
o Hereditary intrinsic platelet d/os
o Idiopathic (Immune) Thrombocytopenic Purpura (ITP)
o Thrombocytopenia due to Splenic Sequestration
o Thrombocytopenia: Other causes: immunologic and non-immunologic
o Thrombotic Thrombocytopenic Purpura: (TTP)
o Von Willebrand’s Dz
• What are normal platelet counts? Lifespan?
o 140,000-440,000/uL
o Varies according to menstrual cycle phase
o Dec in near-term pregnancy
o Increases in response to inflammatory cytokines
o Life: 7-10 days, eventually destroyed by the spleen.
• What are the general types of platelet d/os?
o include increased numbers, decreased numbers, and platelet dysfunction
• what are causes of thrombocytopenia?
o failure of production o inc sequestration o inc destruction or consumption o inc dilution o Combo of above o Quinine, drugs, liver dz, DIC, pregnancy, preeclampsia, ITP, HIV, more
• When does thrombocytopenia cause increased bleeding?
o the lower the platelet count
o < 50,000/uL: Easy minor bleeding, major bleeding risk inc
o <10,000 mb asx
• How is thrombocytopenia diagnosed?
o CBC
o coagulation studies (normal)
o smear- platelet ct
o Suspect platelet dysfunction if CBC, INR and PTT are normal
• How can you ddx thrombocytopenia vs platelet dysfunction?
o penia: smear may suggest cause; Abnormalities may require BM aspiration
o dysfunction: Hereditary cause suspected if hx of easy bleeding and prolonged bleeding after surgery; VWF studies mb done
• What is acquired platelet dysfunction?
o Due to aspirin, NSAIDS, other platelet inhibiting drugs, or systemic d/os (HIV, hepatitis C)
o Very common
o Suspect if single incidence of prolonged bleeding occurs, and other possible diagnoses are eliminated
• What are hereditary intrinsic platelet d/os? 3 types? Dx?
o Suspect in pts with lifelong bleeding d/os but normal platelet ct and coag studies
o Three main types:
o Most common: D/os of platelet activation
o Glanzmann’s Thrombasthenia: rare AR d/o
o Bernard-Soulier Syndrome: rare AR d/o
o Dx: platelet aggregation test results will differentiate the d/os
• What is idiopathic immune thrombocytopenic purpura (ITP)?
o AI d/o with inc platelet destruction
o Bimodal age distribution, children and >60yrs
o Acute and self-limited in children (often triggered by viral illness)
o Chronic in adults
• What is cause of ITP? Ssx? Ddx?
o HIV; Hep C; CMV; Drugs; Idiopathic loss of peripheral tolerance
o Ssx: Petechiae on dependent areas of the body (affected by gravity, feet, etc), mucosal bleeding, conjunctival hemorrhages; mb SM
o ddx: vasculitis purpura, hemophilia, thrombocytopenia, TTP
• how is ITP diagnosed?
o Suspect in pts with unexplained thrombocytopenia
o Low platelet ct, with otherwise normal CBC
o BM exam if other abnormalities are present in smear
o = normal or possibly with increased megakaryocytes
• What is thrombocytopenia due to splenic sequestration?
o Platelet ct usu > 30,000
o Occurs in d/os that produce SM:
o Advanced cirrhosis
o MF or myeloid metaplasia have lower cts
• What are 2 other causes of thrombocytopenia?
o Immunologic: Blood transfusion; CT and lymphoproliferative d/os; Drug-induced
o Non-immunologic: ARDS; Gram Negative sepsis; HIV
• What is thrombotic thrombocytopenic purpura (TTP)?
o Platelets destroyed by deposited fibrin strands in small vessels
o Thrombi form in multiple organs
o High fatality rate if left untreated
• What causes TTP?
o Def in plasma enzyme ADAMTS13
o Hemorrhagic colitis from E. Coli O157:H7 or certain strains of Shigella
o Pregnancy
o Drugs (quinine, cyclosporine, mitomycin C)
o AI: SLE, scleroderma, anti-phospholipid
o Many cases idiopathic
• What are ssx of TTP?
o Fever, organ ischemia (with varying severity)
o Ischemia manifests as: Confusion, coma, sz, HA; Abd pain; Arrhythmias, Chest pain
• How is TTP diagnosed?
o Suspect in pts with anemia, thrombocytopenia and sxs o UA o smear o Retic ct o Serum LDH o Renal function o Serum bilirubin (direct and indirect) o Coombs’ test o Dx suggested by anemia, thrombocytopenia, RBC fragments on blood smear, evidence of hemolysis (falling Hb, polychromasia, elevated retics, negative Coombs), renal abnormalities
• What is hemolytic uremic syndrome?
o HUS refers to TTP in children with enterohemorrhagic infection (E. Coli O157:H7 or certain strains of Shigella)
o Usu spontaneously remits
o Untreated cases dt other causes often fatal
o Most pts have only one incidence of TTP-HUS
• What is Von Willebrand’s dz?
o Hereditary (AD) bleeding d/o; impaired synthesis of VWF o prolonged bleeding time and mild to severe factor 8 def
• What are ssx of VWD?
o Usu mild to moderate sxs
o Mild skin and mucosal bleeding, easy bruising
o Menorrhagia
o Prolonged bleeding after surgery
• How is VWD diagnosed?
o Suspect in pts with bleeding d/os, esp if family hx
o Screening coagulation tests mb borderline normal (normal INR, normal or slightly prolonged PTT)
o Prolonged bleeding time
o Normal platelet ct
o Definitive dx: Plasma VWF antigen, VWF activity, and Factor 8; All will be depressed between 15-60% of normal; VWF antigen mb 40% below normal in healthy people with Type O blood
o ASA will seriously prolong the bleeding time
• What is hemostasis?
o the arrest of bleeding from an injured blood vessel
o Requires activity of vascular, platelet, and plasma factors
o Abnormalities in any factors may result in excessive bleeding or thrombosis
• What are vascular factors of hemostasis?
o Local vasoconstriction reduce blood loss from trauma
o Extravasation of blood into surrounding tissues compresses injured vessels
• What are platelet factors of hemostasis?
o NO and prostacyclin promote blood fluidity, dilate vessels, prevent platelet adhesion
o Production stops if endothelium is injured
o Platelets aggregate and adhere to damaged intima:
o Adhere first to VWF in endothelium
o Platelet activation: Plts release mediators including ADP, and cause COX-mediated conversion of arachidonic acid to TxA2; cause platelet aggregation
o Fibrinogen binds and helps connect platelets together
o Thrombin converts fibrinogen to fibrin to further stick platelets together and to the damaged endothelium.
• What are plasma factors of hemostasis?
o interact to produce Thrombin
o In vivo coagulation is predominantly through Extrinsic pathway.
o Injury -> VIIa/TF activates Factor X andIX; IXa and VIIIa combine to form more Xa.
o X activation is required for normal hemostasis, and is affected by def of XIII and IX
• What are the regulatory mechanisms that prevent uncontrolled coagulation?
o Inactivation of coagulation factors by protease inhibitors
o Fibrinolysis via dissolution of fibrin by the proteolytic enzyme plasmin
o Plasminogen activators (to plasmin): tPA, urokinase, streptokinase
o Regulation of Fibrinolysis by Plasminogen Activator Inhibitors (PAIs), and plasmin inhibitors
o Primary PAI: PAI-1 inactivates tPA and urokinase
o Primary plasmin inhibitor: α2-antiplasmin
• What are signs of a pt with a possible bleeding d/o?
o Evaluate pts with ssx of unusual bleeding or if lab abnormality suggests a bleeding d/o (usu found incidentally) o Unexplained epistaxis o Menorrhagia o Prolonged bleeding after minor cuts o Easy bruising or petechiae o Unexplained gingival bleeding
• What Q’s should you ask about hx of bleeding d/os?
o Systemic dzs associated with defects in coagulation or platelets
o Ingestion of drugs, including NSAIDS
o Excessive unusual prior bleeding (including prolonged bleeding time, menorrhagia, epistaxis, hematuria, GI bleeding, hemoptysis); Suggests thrombocytopenia
o FHx of bleeding d/os; Absence does not preclude a genetic d/o
• What PE should be done for bleeding d/os?
o Exam skin and mucosal surfaces for signs of bleeding
o Look for joint tenderness or swelling
o If severe, may see signs of hypovolemia or shock
o Signs of anemia
• What 2 tests should be done for bleeding d/os?
o Platelet count (PT/INR, PTT )
o bleeding time
• What mb seen on platelet count for bleeding d/os? Factors?
o PT (normal 10-13 sec): extrinsic and common pathways: VII, X, V, prothrombin (II), fibrinogen (I) o PTT (normal 28-34 sec): intrinsic and common: XII, XI, IX, VIII, X, V, prothrombin and fibrinogen o Heparin prolongs PTT o Auto-abs to Factor VIII prolong PTT (Hemophilia) o Prolongation of PT or PTT may indicate a Factor def or presence of an inhibitor o Factors must be at least 70% def to see a prolongation of PT/PTT o Abnormalities of either should lead to testing of specific factors to narrow down ddx
• How are bleeding time results interpreted?
o controversial due to many factors that can compromise reliability, including use of aspirin or NSAIDs
• what are the thrombotic d/os/ thrombophilias?
o Factor V Leiden mutation (APC Resistance)
o Proteins C and S Def
o Antithrombin Def
o Prothrombin 20210 Gene Mutation (Factor II Mutation)
o Antiphospholipid Ab Syndrome (Lupus Anticoagulant)
o Hyperhomocysteinemia
• what are the genetic causes of increased propensity for venous thromboembolism?
o Factor V Leiden mutation
o Prothrombin 20210 gene mutation
o Def of protein C, S, Z or antithrombin
o Hyperhomocysteinemia
• What are the acquired causes of increased propensity of venous/arterial thrombosis?
o Heparin-induced thrombocytopenia/thrombosis
o Anti-phospholipid abs
o Hyperhomocystinemia (dt B12, folate, or B6 def)
o D/os/Environmental/Lifestyle factors:
o Post-surgical stasis or prolonged immobilization
o Heart failure
o Pregnancy
o Obesity
o Tissue injury from trauma or surgery
o Neoplasms
o Sepsis or severe infection
o Oral Contraceptives containing estrogen
o Atherosclerosis
o Cigarette Smoking (not in Merck)
• What is Factor V Leiden mutation (APC resistance)?
o Factor V Leiden is most common Factor V mutation and increases the tendency to thrombosis.
o Homo riskier for thrombosis than hetero
o 5% prevalence in European populations. Rarely in Asians or Africans.
o DVT and/or PE with no provocation
o Present in 20-60% of pts with spontaneous venous thrombosis
• How is Leiden diagnosed?
o Screening with PTT
o Functional plasma coagulation assay
o Molecular analysis of Factor V gene
• What are protein C and protein S def?
o promote venous thrombosis
o Het def is prevalent in 0.2-0.5%; 75% get venous thromboembolism
o Homo def is obvious neo-natally (neonatal purpura fulminans).
o C Sx: Venous thromboembolism, warfarin induced skin necrosis
o S Sx: Venous and arterial thrombosis.
o Mb acquired, with liver dz, chemo, DIC, warfarin therapy
o Dx: functional plasma coagulation assays
• What is antithrombin def?
o Antithrombin inhibits thrombin, factors Xa, IXa, and XIa.
o Het def prevalence 0.2-0.4% (1/2 get venous thrombosis)
o Homo: fatal to fetus
o Acquired def in DIC, liver dz, nephrotic syndrome, heparin therapy
o Dx: Plasma inhibition of thrombin in the presence of heparin
• What is Prothrombin 20210 Gene Mutation (Factor II Mutation)?
o inc plasma prothrombin levels, inc risk of thrombosis.
o Het def has 2% prevalence in whites, 0.5% in African Americans, rare in Asians.
o Dx: DNA test for Factor II mutation
• What is Antiphospholipid Ab Syndrome (Lupus Anticoagulant)?
o Predisposed to AV thrombosis, stroke, DVT and PE
o Only a minority of pts have recurrent thrombotic problems
o Dx: Prolonged PTT (paradoxical response); Blood test for presence of Lupus Anticoagulant/APA
• What is Hyperhomocysteinemia?
o May predispose to AV thromboembolism
o hi homocysteine contributes to endothelial cell injury
o Homo cystathionine β-synthase def results in increase in plasma homocysteine levels > 10 fold
• What are the coagulation d/os?
o Disseminated Intravascular Coagulation (DIC)
o Hemophilias
• What are causes of abnormal bleeding?
o D/os of coagulation system: o Acquired causes o Hereditary causes o D/os of platelets o D/os of blood vessels
• What are acquired causes of bleeding d/os?
o Vit K def
o Liver dz: Impaired clotting factor synthesis; PT/INR and PTT will be elevated; May see excessive fibrinolysis; Dt increased synthesis of α2 antiplasmin
o DIC
o Circulating anti-coagulants
• What are hereditary most common causes of bleeding d/os?
o Hemostasis: VWD
o Coagulation: hemophilia
• What are the circulating anticoagulants?
o Autoabs that neutralize clotting factors or inhibit protein-bound phospholipid
o Factor VIII anticoagulants:
o 15-35% of Hemophilia A pts; Complication of therapy
o May occur in other AI dzs
o May results in life-threatening hemorrhage
• What is Disseminated Intravascular Coagulation (DIC)?
o Widespread activation of the clotting system and consumption of all the clotting factors resulting in bleeding
o excess generation of thrombin and fibrin deposition, then factor depletion
• what causes DIC?
o Obstetrical complications: Therapeutic abortion; Retained dead fetus or other conception products
o Infx: Activated by bacterial toxins or tissue products in circulation
o Malignancy: Usu adenocarcinomas of pancreas, prostate
o Shock from any cause
o Common in severe dzs and terminal states, also after large bone fractures and surgery
• What are ssx of DIC?
o Mb rapid, or slow-evolving
o Slow evolving: possible sxs of venous thrombosis and PE
o Severe, rapidly evolving:
o Caused by thrombocytopenia and clotting factor depletion
o Persistent bleeding at skin puncture sites
o Ecchymoses at injection sites
o Serious GI bleeding may occur
o May see intravascular hemolysis
• How is DIC diagnosed? Slow? Rapid?
o Suspect in pts with unexplained bleeding or venous TE (esp. with predisposing condition)
o Platelet count, PT/INR, PTT, Fibrinogen and D-dimer must be done
o Slow: mild thrombocytopenia, normal to prolonged PT/PTT, normal or reduced fibrinogen, increased D-dimer; 2 consecutive measurements showing evolution of values will help with the Dx.
o Rapid DIC: severe thrombocytopenia, more prolonged PT/PTT, rapidly declining fibrinogen, high D-dimer; Use Factor VIII level to differentiate b/w massive hepatic necrosis (elevated) and DIC (reduced)
• What are hemophilias?
o Inherited bleeding d/os with clotting factor def
o Most commonly Factor VIII (hemophilia A) or IX (hemophilia B) is involved
o 80% Hemophilia A
o A and B are identical clinically
o Inherited sex linked recessive trait with bleeding seen only in males
o Hemophilia pts have < 5% of normal Factor VIII and IX levels
o Normal hemostasis requires > 30%
• What are ssx of hemophilias?
o begins in early childhood and persists
o Variable severity
o Serious hemorrhage from minor injuries
o Hemarthrosis is virtually diagnostic, pain occurs with bleeding
o Hematuria and easy bruising very common
• How is hemophilia diagnosed?
o Suspect in pts with recurrent bleeding, unexplained hemarthroses, or prolonged PTT
o Must do: PT/PTT, platelet ct, factor VIII and IX assays.
o PTT will be prolonged, PT and platelet ct normal.
o Factor 8 and 9 determine type and severity of Hemophilia:
o less than 1% of normal: severe bleeding throughout life
o 1-5% of normal: Moderate, bleeding after minimal trauma
o 5-25% of normal: Mild, excessive bleeding after surgery, dental extraction
o around 50% seldom have spontaneous bleeds (carriers)
o Factor VIII may also be reduced in von Willebrand’s dz.
o Run VWF assays in pts with hemophilia A
• How can you prevent complications with hemophilia?
o Avoidance of aspirin and NSAIDS
o Regular dental care to avoid extractions
o Use of oral or IV drugs rather than IM, which causes hematomas
o Counseling about importance of injury prevention where possible
• What are the bleeding d/os due to abnormal blood vessels?
o Dysproteinemias
o Hereditary Hemorrhagic Telangiectasia (HHT)
o Purpura Simplex (easy bruising)
o Senile Purpura
