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HEMATOLOGY—1 D-Dimer: Tests for lysis of clots (fibrinolytic activity). Test is Systematic Approach to monoclonal Ab to cross linked D regions of Bleeding Disorder degraded fibrin. 1st Cross linking: Thrombin generation cross- Is there a problem with the pts platelets? linking of fibrin clot via thrombin activation of Thrombocytopenia or platelet functional defect Factor XIII. Platelet count, bleeding time 2 Degradation of fibrin: Fibrinogen degradation by nd Does the pt have an inherited coagulopathy, single plasmin Fibrin factor deficiency? PPP or Plasma Protamine Paracoagulant: Measures Factor VII, VIII, X, V, XI, fibrinogen. monomer when clots are present. Was used PT, PTT originally as test for DVT. Does the pt have a deficiency of several of the Vit-K Anti-Thrombin III: Produced in liver. Measured as % dependent Coagulation factors? of Nl. Vit-K deficiency, liver dz, warfarin therapy DIC: Antithrombin III < 60% of Nl. < 10-30 % DIC PT, PTT, TT and Fibrinogen assay -2 Antiplasmin: Produced in liver. Is there a Circulating Anti-coagulant present? Rapidly inactivates plasmin irreversibly. Test for rate of Heparin, factor VIII or IX Ab, lupus anti-coagulant plasmin generation in fibrinolysis. PTT with 1:1 mix, TT, Reptilase time Severe liver dz: production of -2 Antiplasmin Does the pt have a consumptive coagulopathy? inhibition of plasmin TTP, HUS, vasculitis, sepsis, OB complications, DIC: in alpha antiplasmin. trauma, liver dz. DIC screen: Plt count, PT, PTT, TT, fibrinogen, antithrombin III, -2 antiplasmin, d-Dimer assay, Platelet Dysfunction blood film, PPP Acquired Abnormalities of Platelet Function Medications: ASA, other NSAIDS, clopidogrel, Clinical Approach to penicillins Systemic Disorders Bleeding Disorders 1) Chronic renal failure and uremia: Uncleared Platelet Tests metabolic byproducts act as inhibitors of platelet function. BT. Corrected by hemodialysis. Platelet count: Inspected by Wright’s smear. 1 platelet 2) Cardiopulmonary bypass surgery: Aggregation per 20 RBC. Normal between 150,000 and response to ADP and loss of granule contents. 300,000. False low levels can occur because of 3) Antiplatelet antibodies poor anticoagulation of sample, or presence of EDTA. Hematologic Dz Bleeding Time: To detect significant defect in Plt 1) CML function. Direct relationship between Plt # and BT. 2) Leukemias and myelodysplastic disorders: BT. Also Used to detect a functional defect in a pt w/Nl plt defects in epinephrine-induced aggregation and count. Uremia and ASA therapy prolong BT. Also dense alpha granule function. to detect pts w/vWD. 3) Multiple myelomas and other dysproteinemias: Coagulation Tests: Congenital Disorders of Platelet Function Partial Thromboplastin Time: Intrinsic and common 1) Deficiencies of agonist receptors: ADP, epi, pathways: XII, XI, IX, VIII, X, and V. collagen. Normal: 25 to 38 sec. 2) Deficiency of structural abnormalities of adhesion Prolonged by lack of any of the factors in the int or receptor. common pathway. Factor deficiencies must be 3) Signaling for proteins required for platelet severe to affect the assay. aggregation More sensitive to heparin, and anti-phospholipid 4) Deficiency of platelet procoagulant activity antibody. INTRINSIC PATHWAY Storage pool deficiencies: PaTTI Has XII XI IX VIII Prothrombin Bernard-Soulier syndrome: deficiency of GP Ib-V-IX, giant platelets, thrombocytopenia. X Xa + V Glanzmann thrombasthenia: Autosomal recessive. II VII Thrombin Moderate bleeding. Lacks IIb/IIIa (no fibrinogen EXTRINSIC PATHWAY PeTE’s Car binding). PLA-1. Aggregates with ONLY Prothrombin Time: Extrinsic and common pathways. Ristocetin. Most sensitive for factor VII. More sensitive to multiple deficiencies of Vit-K dependent liver factors. Thrombocytopenia INR: standardized method of expressing prolongation. PT 1 to 1.5 than control factor below 20% of Production Disorders normal. Inherited: Other causes of prolongation: large amounts of heparin Fanconi’s anemia & fibrinogen. May be if blood is stored too long TAR syndrome prior to testing Rubella May-Hegglin anomaly: bizarre giant Plts and basophilic Tests of Fibrinogen inclusions in WBC Thrombin Time: Wiskott-Alsrich syndrome. Measures conversion of fibrinogen to fibrin. Prolonged TT: or Abnl fibrinogen and levels of Acquired: fibrin degradation products. Drugs: thiazide diuretics, estrogens DIC and liver dz: sensitive indicator EtOH Heparin: Very small amounts of heparin can Viral Infections dramatically TT by inhibiting the added Any cause of pancytopenia thrombin. Infiltrative dz of BM: Carcinoma, leukemia, lymphoma, myelofibrosis, Osteopetrosis, and military Tb. 2—HEMATOLOGY Radiation Tx and myelosuppresive therapy 1) Effective management of underlying dz. Megaloblastic anemia 2) FFP: Replacement of coagulation factors. 3) Cryoprecipitate: Replacement of fibrinogen. Treatment: Plt transfusions. HLA matched. Must be Isolated Platelet Consumption tailored to meet pts needs. Each unit of pheresed Plts should plt count by 50,000. Need to beware Pts w/vascular disorders such as vasculitis, HUS, and of alloimmunization. TTP. Differential: Symptoms and signs of organ damage Disorders of Distribution Renal failure from glomerular thrombosis Splenomegaly: Spleen as storage organ for Plts. Can Skin infarction splenic trapping of Plts. Plt survival is Nl & Multifocal brain infarction little risk of thrombocytopenia related bleeding. RBC hemolysis is common and is most marked in pts Splenomegaly should not plt to < 40,000. with HUS. Bleeding is not a major component Myeloproliferative dz or 1* thrombocythemia. unless plt count < 20,000. Treatment: Not normally related to abnormal bleeding. Treatment: Plt transfusions not normally needed. Only if plt 1) Prednisone, Methylprednisone and Plasmapheresis count 20,000 or 30,000. w/myelofibrosis can w/FFP exchange. be difficult to predict whether splenectomy will 2) Should not receive Plt transfusions or Antiplatelet help or hurt. After splenectomy plts may > 1 agent unless CT evidence of large intracranial million. bleed. Infusion can accelerated organ damage. Thrombotic Thrombocytopenic Purpura Destruction Disorders (TTP) DIC Infection ITP HUS Non-immune consumption of platelets, Plt thrombus Post-transfusion purpura Kasabach-Merrit formation, & organ damage. Can occur after chemo Syndrome or BMT or post-partum. Can be idiopathic. Drug Ristocetin Malaria Cause: Etiology not clear. Drug sensitivity: quinine, quinidine ?Viral illness Autoimmune Thrombocytopenia ?Endothelial damage release of vWF Acute hemolytic reaction: erythroblastosis ?Ab to protease that clips vWF. Left w/too large vWF plt clumping. DIC: Clinical: Pentad. Abnl bleeding w/thrombocytopenia and Fever: present at admit in ~ 50%. hypofibrinogenemia. May demonstrate gross Thrombocytopenic purpura or other bleeding: Non- hemorrhage or thrombosis, or both. immune consumption of plts. Hyaline-platelet 1) Consumption of coagulation factors exceeds complexes form in small vessels, trapping platelets. production capacity. Neurologic: CN palsies, dysphasia or aphasia, paresis, 2) Fibrin deposits in microcirculation confusion, stupor, coma, and seizures. Renal: proteinuria, hematuria, & mild renal Dx: right clinical settings & lab evidence of aggressive insufficiency. coagulation and fibrinolysis. Microangiopathic anemia w/fragmentation: Essential for Clinical: diagnosis Severe, systemic illnesses: esp. true if pt exhibits any Other: SOB, jaundice, abdominal pain. signs of unexplained organ failure or an abnormal bleeding tendency. Labs: Sepsis: Esp. pts with meningococcemia. PT, PTT, fibrinogen, and fibrin degradation products: Nl Shock LDH: Crush injury Haptoglobin: due to intravascular hemolysis. Surgical trauma Widespread malignancy Treatment: Required. W/out will die from severe Hemorrhagic pancreatitis anemia or stroke. Obstetric complication 1) Plasma Exchange w/plasma pheresis: Daily until Intrauterine fetal death respond. Exchange at least one plasma volume per Amniotic fluid embolism day Abrupto placentae. 2) Steroid: Ab production. Unproven benefit. 3) Platelet inhibitor: ASA or dipyridamole. Unproven Smear: benefit. Schistocytes: Fragmented RBC. RBC rubbing 4) Chemotherapy: Vincristine, cyclophosphamide, and across fibrin monomer. Lack does not rule out DIC azathioprine. Second line therapy or for pts who No Plts. Toxic granules and Dohle bodies. refuse exchange. Prognosis: Remission often permanent. Lab Tests: PT/PTT: Prolonged. Due to consumption of coagulation Hemolytic Uremic Syndrome (HUS) factors. Cause: Associated with hemorrhagic colitis, 2* to esp. Plts: 50,000 to 100,000 E-Coli. No CNS abnormalities, marked Thrombin Time: thrombocytopenia, or fragmentation. Bacterial Fibrinogen: Reduced. infection —>release toxins —> damage to D-Dimer: None to depending on degree of 2* lysis endothelial cells —>plt clumping. PPP: (+) Pt is forming clots. Clinical: Children mainly. Pure HUS seen in children VWF: normal. Not consumed. and young adults. Acute renal failure. Smear: Fragmented RBC, and low # of plts. Severity of DIC: Treatment: Antithrombin III: 1) Supportive therapy -2 antiplasmin: 40 to 50% normal severe ongoing 2) May require dialysis. Recovery should be complete DIC. 3) Iv Ig or steroids may be needed. Thrombocytopenic purpura in adults Treatment: Causes: HEMATOLOGY—3 1) Exposure to blood products: surrounding individual deformed corkscrew-shaped 2) Drugs: Quinine, quinidine, and sedormid. Heparin hairs. Easy bruisability and formation of induced IgG antibodies can form and bind to ecchymoses over lower extremities is also seen. heparin. Treatment: Withdrawal of drug. If heparin Bleeding gums and deep intramuscular and needed—> stop all heparin. Danapraoid as alt to subperiosteal hemorrhages may also be present. heparin. 3. Congenital Defects of vessel wall such as hereditary 3) Infections: HIV. Treatment: Can be treated with telangiectasia. AZT. 60% will show response and 50% will have Vasculitis: long lasting improvement. Splenectomy for those 1. Septic or aseptic vasculitis: Sudden appearance of that do not respond, but needs to be done early in dz palpable purpura, preceded by urticarial rash process. Corticosteroids, IV Ig and IV anti-D. May 2. Henoch-Schonlein purpura: rash with fever, only respond to platelet transfusion. Also malaise, polyarthralgia, and colicky abdominal pain. plasmapheresis. Most common in childhood and young adolescence. 4) Malignancies: Lymphomas. HL, NHL, and CLL Dysproteinemias: Therapy and Clinical Course: No Tx are associated with production of autoantibodies for pts without definable coagulation defect. Vit C with platelet specificity. deficiency and aseptic vasculitis respond to therapy 5) Autoimmune dz: SLE. Look for arthralgia, arthritis, skin dz, unexplained pleurisy, hepatitis, or Loss of Platelets IBD. Treatment: Best controlled by controlling the Hemorrhage and multiple blood transfusions systemic disease. Corticosteroids may be used Extracorporeal circulation occasionally on a short-term basis. Idiopathic Thrombocytopenic Purpura Von Willebrand Dz: (ITP): Most common congenital bleeding disorder. Cause: Antibody formation vs. plt surface membrane Role of vWF: Helps with platelet activation and Ag. Ab coat is read as abnormal short plt adhesion. Also is carrier for factor 8. Not used up survival time. Need to exclude medications as in acute reactions. cause. Type 1 vs. Type 2: Look at multimeric structure to help Clinical: Can be acute. Usually starts as chronic. distinguish from type I and type II. Presents because of abnormal bleeding. Ristocetin-induced platelet agglutination: Smear: normal plts. Decreased Agglutination: BM: Increase in Megakaryocytes. vWD: I, IIa, IIc, and III Treatment: ITP Storage pool dz 1) If plt count ~50,000 watch. No treatment. Bernard-Soulier Synd AML 2) Steroids: High dose. ASA ingestion Infectious Mono 3) Plt transfusions: If evidence of intracranial Cirrhosis Af-Am population hemorrhage. Increased Agglutination: 4) Ig: if plt Transfusion or steroids do not work. May vWD IIb Psuedo vWD require repeat therapy. Plasma Multimeric Structure: 5) If > 3 or 4 mo, splenectomy should be considered. Platelet Multimeric Structure: 75 to 80% will achieve permanent remission. vWD: Type 1: Should work. 6) Serious refractory cases platelet transfusion. Quantitative defect in plasma vWF levels. Autosomal Dominant. Autoimmune Thrombocytopenia Cause: Defect in vWF release from Weibel-Palade Neonatal thrombocytopenia bodies of the endothelial cells. Plts & endothelial Clinical: Result of alloimmune sensitization during stores of vWF are Nl. Have release of vWF with pregnancy or as a result of maternal autoimmune administration of DDAVP. thrombocytopenia. Clinical: Treatment: When mild does not require therapy. Severe Epistaxis Ig therapy. Binds antibody. Washed platelet Menhorragia. ♀ more common. Clinical severity transfusion good. variable. In symptomatic pts, vWF:Ag and vWF activity are reduced to below 50% of normal. Postviral thrombocytopenia in children. Usually self Blood type O show normal low levels so should not limited lasting less than 1 to 2 weeks. be confused with pts w/vWD. Treatment: If plt count is above 30,000 and no Lab Tests: mucocutaneous bleeding —>watch and wait. If Bleeding time: Prolonged. below 10,000 should be hospitalized and given IV PT: normal immune globulin. Also high dose glucocorticoid. PTT: Prolonged. Lack of factor VIII Splenectomy reserved for only children VIII:Ag: Absolute experiencing life threatening bleeding. 70% VIII:C: Absolute remission. Ristocetin-induced Plt agglutination: or Nl. Vascular Purpura Crossed Immunoelectrophoresis: Normal. Response to DDAVP: Restore hemostasis to normal. Clinical Features: Clinical pattern of bleeding, relationship to minor trauma and drug ingestion, Treatment: dietary habits, and symptoms or signs of systemic 1) DDAVP: Show good response with administration. dz. PE: Skin atrophy and multiple bluish-colored 2) vWF replacement: Cryoprecipitate. 1 bag per 10 kg ecchymoses on forearms and backs of hands. of body weight twice a week. Hyperpigmentation. Amyloidosis—plaques of 3) Avoidance of ASA containing compounds. papules of waxy skin. Lab Studies: Normal coagulation studies. Platelet Type IIa vWD: count, PT, PTT. Qualitative defect in plasma vWF. Autosomal dominant Differential: Inability of form or stabilize large multimers. Structural Abnormalities: 1. Senile/Steroid Purpura: atrophy of skin and Clinical: subcutaneous tissue due to collagen breakdown. Bleeding time: Prolonged 2. Scurvy: Vit-C deficiency. Needed for collagen Crossed Immunoelectrophoresis: Abnormal. biosynthesis. Perifollicular hemorrhages Ristocetin cofactor activity: No response. 4—HEMATOLOGY Response to DDAVP: No response. Factor VIII R:Ag 1:1 mix: Evaluate factor deficiency vs. inhibitor. , but multimeric abnormality is not corrected. Immunologic measurement of level of factor antigen and assay of coagulant activity Treatment: DDAVP contraindicated. Give vWF Treatment replacement. 1. Rapid and effective factor replacement. Factor should be given regardless of location. Prophylaxis Type IIb vWd should be reserved for anticipated bleeding (surgery Autosomal dominant. Intrinsic abnormality of von or high-risk physical activities). Willebrand factor tissue binding. 2. W/recombinant factors can give regular doses of Abnormal vWF with increased affinity for the platelet factor. GPIb/IX receptor. This leads to a lower plasma 3. Self infusion as soon as bleeding episode is level of these larger dimers. The vWF are clumped suspected. onto the platelet greater platelet aggregation in 4. CNS bleed get factor to 100% then take history. circulation, aggregate removal, thrombocytopenia 5. Immunologic measurement factor antigen & assay and suffer from bleeding tendency. of coagulant activity. 6. DDAVP: release of vWF circulating VIII Clinical: coagulation. Bleeding Time: Prolonged Ristocetin-induced Plt agglutination: Hypersensitive Hemophilia B (Christmas Factor) IX response. Cause: Factor IX levels less than 1% severe Ristocetin cofactor activity: bleeding. Results from a number of genetic Response to DDAVP: Transient correction of mutations. Most are mutations nonfunctional multimeric abnormality. Bleeding time may be protein. Normal levels of protein. corrected. Clinical: Similar spectrum of dz as Hemo A. Bleeding into the large joints of the upper and lower Treatment: extremities. Begin once the affected child reaches 1) DDAVP can worsen condition by vWF release toddler and then increases as the child becomes and worsening the thrombocytopenia. more active. Chronic synovitis, destruction of 2) vWF replacement. cartilage and bone, and a progressive flexion contracture. Bleeding into muscles. Hematuria, intracranial hemorrhage, mucous membrane Liver dz & the coagulation bleeding, and bleeding following minor trauma or system: surgery. Lab Studies: ↑ PTT/↑ BT/Normal PT. Then mixing All clotting proteins made in liver except factor VIII factor deficiency vs. inhibitor. Immunologic which is made in the endothelium. W/dz will get no measurement of level of factor antigen and assay of production of fibrinogen and other factors (except coagulant activity. 8) increased bleeding. Treatment: FFP, purified factor IX, recombinant IX. Vit K deficiency: Inhibitor of factor VIII (or IX) identified Role: Vit K dependent— 1:1 mix of pt plasma and normal plasma to determine if Procoagulant: 7, 9, and 10. prolonged PTT can be corrected. Hemo A: Anticoagulant: Proteins C and S. deficiency of factor VIII will show partial or Lab: ↑ PT/ ↑ PTT Then mixing to look for inhibitor. If complete correction when normal plasma is added. no correction in PTT then determine if Vit-K lack Pt with factor VIII inhibitor or lupus anticoagulant or liver dz. Pick factor made in liver and not Vit-K will not correct the defect. dependent: 5. If liver dz then ↓ 5 . If Vit-K then 5 Low Responder: Factor 8 concentrates up to high levels. will be normal. If poor response then have a … Causes: Poor Diet. Malabsorption. Vit A or E High Responder: Wait for minor bleeding episodes. administration. Drugs: Antibiotics, Cholestyramine, Mineral Oil. Liver Dz. Depletion can occur over as short as 1 week. NATURAL Treatment: Administration of Vit-K. Will take 1 day to become effective. ANTICOAGULANTS Protein C Non-Vit-K : 11, 12. Co-factors: 8 and 5. Fibrinogen. Serine protease that is Vit K dependent Made in the 13. liver. tPA Thrombin + intact endothelium activated Protein C Degraded in liver. When have function in liver cleaves Va and VIIIa Deficiency: 2-5% w/thrombosis HEMOPHILIA 15% of young adults w/thrombosis. Coumadin induced skin necrosis during loading. Hemophilia A VIII Treatment: Long-term PO anticoagulants. Inversion of factor VIII gene. X Chromosome. Variety of mutations lead to variety of levels of disease. Protein S low levels of factor VIII antigen and activity. Vit K dependent cofactor. Not a protease. Clinical: Helps bind APC to phospholipid. 1) Severe hemophilia have factor VIII activities < 1 Possible arterial thrombosis. % of normal. Dx frequent, spontaneous Antithrombin III hemorrhages into joints, muscles and vital organs. 2) Factor activity level of 1 to 5% of normal is enough Serine Protease Inhibitor made in liver to reduce the severity of the disease. They are at Autosomal dominant: 1/2000 risk of bleeding with surgery or trauma. Women Thrombin:Antithrombin complex inhibits 75% of may also be at risk during surgery. thrombin. Lab Studies: Heparin enhances reaction 2000x DVT PTT: prolonged Treatment: FFP or antithrombin III concentrates for BT: prolonged short-term replacement therapy. Long-term oral PT: normal. anticoagulants. HEMATOLOGY—5 Factor V Leiden Base pair substitution Resists APC degradation. 6% of normal 40% of DVT pts. Thrombosis at any time. LUPUS LIKE ANTICOAGULANT Primary: Ab directed toward phospholipid. Thromboses in 25-60% of pts. Recurrent fetal death. Secondary: 5-10% SLE. Drugs. Autoimmune. HIV. Virus. Malignancy. Inhibits Xa/II from binding phospholipids. Lab Tests: Prolonged PTT not corrected with 1:1 mix. Dilute Russell Viper Venom Test: Prolonged in presence of APL Ab. Confirm by correction with platelets. Most sensitive. Diagnosis: Clinical evidence: Lab evidence: 2(+) Ab tests separated by 6 weeks. Treatment and prognosis No good long term studies on pts w/lupus Ab to look at what is their incidence of venous or arterial thrombosis. Have looked at pregnant women. Steroid have helped. Pre-operative: Make sure no underlying factor VIII or II antibody that can cause very severe problems. Having the antiphospholipid ab does not risk perioperatively. THROMBOCYTOSIS Secondary or Reactive: Acute blood loss Postpartum Infection Post-traumatic After splenectomy Exercise Post-Op state Drug epinephrine Ovulation Sarcoidosis Adrenal Hyperplasia Osteoporosis Hemophilia A After thrombocytopenia: Pernicious anemia, acute thrombocytopenic purpura, EtOH-induced thrombocytopenia, drug-induced thrombocytopenia. Chronic: IBD RA Hodgkin’s Dz Carcinoma Osteogenic sarcoma Retinoblastoma Mesothelioma Fe deficiency Splenic Atrophy Chronic hemolytic anemia sp splenectomy
"Bleeding Disorders - MedEd"