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  1. 1. Hematology Archer’s Online USMLE Reviews www.CcsWorkshop.com All rights reserved
  2. 2. Anticoagulants      Heparin Low Molecular Weight Heparin Warfarin Direct thrombin inhibitors – leuperidin, argatroban Factor Xa Inhibitors - fondaparinaux
  3. 3. Heparins Antithrombin 3 is a naturally occuring slow inhibitor of clotting pathway. Heparin binds to AT-3 and converts it from slow to rapid inhibitor by forming a ternary complex with AT-3 and thrombin    Unfractionated Heparin : Unfractionated heparin is a heterogeneous mixture of polysaccharide chains with a mean molecular weight of 15,000 Daltons. Given I.V. Requires Inpatient Rx. Higher incidence of Throbocytopenia and osteopenia. Monitored by measuring APTT LMWH: Derived from heparin. Molecular weight-5000 D. Can be given twice daily doses on OP basis. Less incidence of throbocytopenia and osteopenia. LMWHs have more anti factor X a activity than UF heparin. LMWH activity is monitored by factor Xa activity. Heparins can cause Hyperkalemia
  4. 4. Heparin Induced Skin Necrosis        Affects middle age women with history of thrombotic disease Characterized by the formation of one or more painful red plaques or necrotic skin lesions. 5 days or more after starting heparin treatment. Earlier in those treated previously with heparin. Some patients develop thrombocytopenia when lesion first appears, often with paradoxical thrombosis.(HIT)  Is not always associated with thrombocytopenia A rare complication of heparin characterized by immune complex formation and thrombosis. HIT Should be suspected if the patient develop skin necrosis in areas of SQ injection or IV site. Rx – stop Heparin + start Direct thrombin inhibitors or heparinoids ( Leupiridin or Argatroban )  ( i.e; treat like HIT)
  5. 5. Warfarin Mechanism of action Antagonist Skin necrosis Uses INR monitoring Dealing with Supratherapeutic INR on case by case basis Dealing with Sub therapeutic INR ( APLA, OBESITY, WARFARIN RESISTANCE, INTERACTIONS, NONCOMPLIANCE) 
  6. 6. WARFARIN: MECHANISM OF ACTION Vitamin K epoxide WARFARIN Vitamin K reduced Inactive factors II, VII, IX, and X Proteins S and C Active factors II, VII, IX, and X Proteins S and C Prevents the reduction of vitamin K, which is essential for activation of certain factors Has no effect on previously formed thrombus
  7. 7. PLASMA HALF-LIVES OF VITAMIN KDEPENDENT PROTEINS Factor II Factor VII 72h 6h Factor IX 24h Factor X 36h Peak anticoagulant effect may be delayed by 72 to 96 hours PROTEIN S HALF LIFE : shorter than above
  8. 8. Coumadin Skin Necrosis • • • Warfarin Procoagulant Effect in first few hours can cause warfarin skin necrosis due to thrombosis. Concomitant heparin use can decrease the incidence Patients developing coumadin skin necrosis should be evaluated for Protein C deficiency
  9. 9. Rx   Stop Coumadin Use heparin until the necrotic lesions heal.
  10. 10. Correcting SupraTherapeutic INR Approach!
  11. 11.        Warfarin has a narrow therapeutic index Therapeutic INR typically targeted at 2-3. The risk of bleeding increases significantly when the INR > 4-6. However, the absolute risk is still low at 5.5 bleeding events per 1000 per day Therefore, patients with an INR < 9 and no significant bleeding  Manage by omitting subsequent doses of warfarin, more frequent monitoring of the INR, and resumption of therapy at a lower dose when the INR is therapeutic. When rapid reversal of the INR is needed, fresh frozen plasma, prothrombin complex, or recombinant factor VIIa can be administered. Administration of coagulation factors provides only a temporary solution due to the short half-life of the provided clotting factors (3-4 hours for Factor VII), compared with a duration of action of 2 to 5 days for warfarin, as well as relative instability of clotting factors upon administration. Administration of either fresh frozen plasma or factor concentrates will decrease the PT/INR for 4 to 6 hours  So, complete return to a therapeutic INR will require supplementation with vitamin K
  12. 12. Rxng Supratherapeutic INR      Treatment of a supra therapeutic INR requires a balance between reducing the risk for hemorrhage while minimizing the risk of thrombembolism. Treatment approaches are based on the current INR, presence of bleeding, and the time frame in which reversal is required. Vitamin K1 CAN BE GIVEN to reverse the anticoagulation effect of warfarin. The most appropriate dose of vitamin K1 is the one that lowers the INR to a safe level without resulting in a subtherapeutic INR. High doses of vitamin K1 are effective but may lead to warfarin resistance for a week or more, resulting in an increased risk for thromboembolism. In such cases, heparin should be given until the effects of the vitamin K1 are complete. ( note this point)
  13. 13. Forms of Vitamin K    Available in subcutaneous, IV and oral forms Subcutaneous route  delayed onset and is less predictable. If rapid reversal is desired, the IV route should be utilized, as this route has the fastest onset of action. ( Historically, intravenous vitamin K1 has been associated with an increased risk of anaphylaxis. A retrospective review of anaphylactic reactions associated with IV vitamin K1 from the Mayo Clinic revealed that the risk of anaphylaxis with vitamin K1 was 3 per 10,000 doses—a rate comparable to all forms of penicillin and less than that of IV iron dextran. If is administered by the IV route, lower doses and slower infusion rates are recommended)   Unless rapid reversal of the INR is critical, oral vitamin K1 is the preferred route of administration. In the United States, oral vitamin K1 is only available as a 5 mg tablet (Mephyton®). Therefore, oral doses prescribed should reflect even divisions of 5 mg (e.g., 2.5 mg).
  14. 14. Forms of Vitamin K Route Advantages Disadvantages IV • Fastest Onset of Action • Subcutaneous • Lower risk of anaphylaxis • Oral • Safest route •Low risk of anaphylaxis •No IV site needed • Must be given by slow IV infusion •Warfarin resistance Delayed onset •Unpredictable response •Least desired route Slower onset of action •Warfarin resistance
  15. 15. Management of Elevated INR in Patients Receiving Vitamin K Antagonists INR Bleeding Present Rapid Reduction Required Management* <5 No No Lower dose by 10% or omit dose; resume at lower dose when INR is therapeutic i.e; 2 TO 3 5-9 No No Omit one or two doses, resume at lower dose by 10%. No Yes — high risk May give vitamin K 2.5 mg orally if at increased risk for bleeding. No Yes—surgery 2-4 mg oral vitamin K1 for reduction of INR in 24 hours; if INR still high, can repeat with 1-2 mg orally. ≥9 No No Hold dose and give vitamin K1 10 mg orally to reduce INR in 24 hours; may repeat vitamin K1as necessary. Resume at lower dose when therapeutic. Any Yes—Serious Bleeding Yes Hold dose, give vitamin K1 10 mg by slow IV infusion, along with fresh frozen plasma, prothrombin complex, or recombinant factor VIIa; vitamin K1 may be repeated every 12 hours. Any Yes—Life Threatening Yes Hold dose, give prothrombin complex along with vitamin K1 10 mg by slow IV infusion; repeat if necessary depending on INR.
  16. 16.    When the INR is elevated in a patient who has been on a consistent dose of warfarin for past few weeks  Always, consider why it is elevated Antibiotics can potentate by causing Vitamin k deficiency. If drug interaction is considered  stop the other drug if possible. If stopping the interacting drug is feasible and if INR < 5, no need to reduce the warfarin dose
  17. 17. Addressing Sub Therapeutic INR Approach on increasing the dose Warfarin Resistance 
  18. 18. Sub-Therapeutic INR    INR< 1.5 – Increase the dose by 10 to 20%, consider extra dose and repeat INR in 4 to 8 days. 1.5 to 2.4 – Increase dose by 5 to 10%. Repeat INR in one to two weeks 2.5 to 3.5 – No change in dose. Repeat INR is the # of consecutive inrange INRs (For example, if a patient has had three consecutive in-range INR values, recheck in 3 weeks. Maximum repeatable period not longer than 4 weeks )
  19. 19. Foods that can cause sub-therapeutic INR  Foods with very high vitamin K content (more than 200 mcg) — Brussel sprouts, chickpeas, collard greens, coriander, endive, kale, liver, parsley, red leaf lettuce, spinach, Swiss chard, black or green teas, turnip greens, watercress. Foods with high vitamin K content (100-200 mcg) include basil, broccoli, butterhead lettuce, canola oil, chives, coleslaw, cucumbers (with peel), green onions, mustard greens, soybean oil.
  20. 20. Scenarios        DVT Pulmonary Embolism DVT prophylaxis Atrial fibrillation Prosthetic Valves Mural thrombus Acute Coronary Syndrome
  21. 21. Deep Vein Thrombosis Pulmonary Embolism
  22. 22. Abnormal Blood Flow Abnormal Vessel Wall Abnormal Blood The Hypercoagulable State Dr. Rudolph Virchow 1821-1902
  23. 23. Deep Vein Thrombosis Clinical associations Immobility Obesity Smoking Cancer Pregnancy Estrogen therapy
  24. 24. Economy class syndrome    Economy-class syndrome is a name used by the media to describe Venous Thrombo-Embolism that can occur in anyone - but has been of particular worry in air travellers. Incidence of DVT & PE increases with the flight distance Prevention tips : Drink fluids, avoid caffeine and alcohol, keep moving legs and wear graduated support stockings designed for travel.
  25. 25. Proximal Distal
  26. 26. Proximal vs. Distal DVT      Thrombosis confined to deep calf veins is Distal DVT where as thrombosis at or above popliteal veins is Proximal DVT. A distal DVT becomes clinically important when it extends proximally Risk of PE is much higher with proximal DVT. Silent PE occurs in about 50% of pts with proximal DVT. All patients with Proximal DVT are at increased long term risk for chronic venous insufficiency. Compression ultrasound is more sensitive to proximal DVT when compared to distal DVT.
  27. 27. Idiopathic DVT    A case of DVT where no evidence of underlying obvious cause such as surgery, trauma or known malignancy is present. Search for a hypercoagulable state in such conditions Hypercoagulable states : inherited or acquired
  28. 28. Evaluating Idiopathic Venous Thromboembolism APPROACH
  29. 29. Hypercoagulabilty – Whom to test?     DVT occurring in a pt < 50 yrs of age Positive Family Hx of Venous thromboembolism Recurrent episodes of unexplained Venous thromboembolism Don’t forget to include Homocysteine When homocysteine levels are elevated in the presence of factor V Leiden or the prothrombin gene G20210A mutation, risk of recurrent thrombosis appears to be increased beyond the risk associated with any one defect alone
  30. 30. Hypercoagulabilty – When to test?   Heparin • Controversial AT-III (heparin vs acute event) • Most coagulation based test for APLA  Hexagonal phospholipid not affected Warfarin • Protein C and protein S • Need to wait 3 weeks before testing protein S • Most coagulation based APLA tests
  31. 31. Hypercoagulable states Inherited -“ The big five” • Factor V Leiden • Prothrombin gene mutation • Protein S deficiency • Protein C deficiency • Antithrombin III deficiency
  32. 32. Factor V Leiden    Most common inherited risk factor Often associated with other risk factors e.g: homocysteine Dramatic increase in risk with estrogens ( OC Pills)
  33. 33. Hypercoagulability states Acquired  Cancer  Antiphospholipid antibody syndrome  Nephrotic syndrome  Inflammatory bowel disease. Etiology: inflammatory cytokines, low protein s  Homocysteine Clues to Acquired state : older age at the time of onset, refractory to Warfarin , both venous and arterial thromboembolism.
  34. 34. DVT and Cancer   Clues – Bilateral DVTs, Arterial and venous thrombosis and Warfarin refractory thrombosis
  35. 35. DVT Diagnosis
  36. 36. Differential Diagnosis • Cellulitis • Knee pathology i.e. ruptured synovial cyst • Calf muscle strain • Calf muscle hematoma
  37. 37. INVESTIGATIONS    Venogram : Gold standard. Rarely performed due to accuracy of non invasive testing. Risks: phlebitis, hypersensitivity, nephrotoxicity, cardiotoxicity Venous duplex ultrasound : non invasive, accurate, first line study in moderate to high risk DVT. Specificity : 95%. Sensitivity 97% for proximal DVT and only 73% for distal DVT. Can identify other pathology e.g.: calf haematoma, bakers cyst, abscesses MRI : 90% sensitive and specific for acute Proximal DVT.
  38. 38. D-Dimer assays    D-Dimer should not be used as a screening test. Can be used as a first line test in pts with low pretest probability for DVT. The utility of D-Dimer is mainly to reduce the number of ultrasound testings. The negative predictive value of a d-dimer assay falls as the pretest probability for DVT increases. An assay with a sensitivity of 80% has a negative predictive value (NPV) of 97.6% in a low-risk patient. However, the NPV of the same assay is only 33% in high-risk patients with a pretest probability of 90% for DVT.
  39. 39. CLINICAL ( PRETEST) PROBABILITY OF DVT WELLS DVT SCORE SYSTEM ( most popular )                 Clinical Parameter Score Active cancer (treatment ongoing, or within 6 months or palliative) Paralysis or recent plaster immobilization of the lower extremities Recently bedridden for >3 d or major surgery <4 wk Localized tenderness along the distribution of the deep venous system Entire leg swelling Calf swelling >3 cm compared to the asympto - matic leg Pitting edema (greater in the symptomatic leg) Previous DVT documented Collateral superficial veins (non varicose) Alternative diagnosis (as likely or > that of DVT ) +1 +1 +1 +1 +1 +1 +1 +1 +1 - 2
  40. 40. Wells DVT Clinical Score ( contd )   Score of Zero – low probability ( 0 to 13%) Score 1 – 2 probability)  - moderate probability ( 13 to 30% Score > or = 3 - high probability ( 49 to 81%probability)
  41. 41. Complications - DVT     Pulmonary Embolism Post obstructive syndrome : pain and edema in the affected limb without new clot formation Chronic venous insufficiency Rarely, thrombosis is massive, causing vascular compromise of the leg due to high venous pressure (i.e., phlegmasia cerulea dolens).
  43. 43. Treatment   Anticoagulation – heparin, warfarin, lmwh – overlapping treatments IVC filters – greenfield filter
  44. 44. OPTIMIZING WARFARIN THERAPY    Dosage to be individualized according to patient’s INR response. Target INR -2-3 Use of large loading dose may lead to hemorrhage and other complications. Initial dose: 2-5 mg once daily Maintenance dose: 2-10 mg once daily Start heparin on day 1 and warfarin in the evening of Day1 or on Day2. Heparin is usually discontinued after 4-5 days. Before discontinuing, ensure INR is in therapeutic range for 2 consecutive days  Monitor daily until INR is in therapeutic range, then 3 times weekly for 1-2 weeks, then less often (every 4 to 6 weeks)
  45. 45. CONTARINDICATIONS AND PRECAUTIONS - WARFARIN      Hypersensitivity to warfarin Condition with risk of hemorrhage Hemorrhagic tendency Protein C & S deficiency Vitamin K deficiency
  46. 46. SIDE EFFECTS      Hemorrhage Skin necrosis Microembolization Teratogenecity : contraindicated in pregnancy Agranulocytosis, leukopenia, diarrhea, nausea, anorexia.
  47. 47. Uncomplicated DVT - OP management Any reason for Hospitalization ? potential probm with home Rx No probm with Home Rx Hospitalize Give BID S.C LMWH + Warfarin Ongoing Evaluation Give 1st dose S.C LMWH Stat Begin Warfarin in Doses 5mg QD Assign a visiting nurse for twice daily injs ( until the pt or family member can inject ) Daily PT and CBC with platelet count. After atleast 5 days twice daily injs of LMWH, a therapeutic INR for 2 consecutive days – d/c LMWH and follow warfarin carefully as per routine for DVT. Repeat physician evaluation by 5-7, if no problem, repeat 1 wk later and as per routine for DVT.
  48. 48. Reasons for hospitalization in DVT     Signs and symptoms of PE Co-existing medical illness – anemia, lung disease, previous bleeding, high risk of bleeding or clotting Depression or any other mental illness that restricts pt’s co-operation and compliance with the home Rx. Insurance problem or other logistic difficulty that limits pt’s access to home Rx, nursing care, monitoring, food & shelter
  49. 49. Duration of therapy ?
  50. 50. Duration depends on risk factor for DVT      Risk of recurrence depends on type of risk factor. If 1st DVT occurred after a major risk factor, recurrence is 3% where as if it occurred after minor risk factor recurrence is 10%  So, stratify pts based on risk factor and then decide duration Major transient risk factors : Major surgery, major medical illness and leg casting. Minor transient risk factors : OC Pills, HRT High risk thrombophilias : Homzygos Prothrombin gene mutation, Homozygos Factor v leiden, antithrombin, protein c and protein s deficiencies and APLA Syndrome Low risk thrombophilias : Heterozygosity for prothrobin gene mutation and Factor V leiden
  51. 51. Recommendations – Duration of Anticoagulant Rx in pts with DVT Patient Risk of recurrence Duration of characteristics (%) Therapy - In the year after discontinuation Major transient risk factor b.Minor risk factor, no thrombophilia a. Idiopathic event, no or low risk thrombophilia d.Idiopathic event, high risk thrombophilia e.More than one idiopathic event f.Cancer, other ongoing risk factor Ref: NEJM, 2004, 351 3% <10% if risk factor avoided. >10% if persistent c. <10% >10% >10% >10% 3 months 6 months Until factor resolves 6 months Indefinite Indefinite Indefinite. Consider long term Rx with LMWH in pts with cancer
  52. 52. Contraindications - Anticoagulant RX Absolute contraindications:  Active bleeding  Severe bleeding diatheses or platelet count< 20,000/mm3  Neurosurgery, ocular surgery or intracranial bleeding in past 10 days Relative contraindications:  Mild/moderate bleeding diatheses or thrombocytopenia  Recent major trauma  Major abdominal surgery in past 2 days  Brain metastases  Gastro/genitourinary bleeding in past 2wks  Endocarditis  Severe hypertension at presentation ( SBP>200 and DBP>120)
  53. 53. Case Study        A 79-year-old man is admitted to the medical ward 3 days status post subdural hematoma drainage, C3 cervical spine fracture, and fixation of multiple extremity fractures sustained in a motor vehicle accident. The patient is now awake and oriented to person, place, and time, but is a lower cervical spine incomplete quadriplegic. Physical examination reveals some minimal sensation in the legs, but no ability to move the extremities. There is a Foley catheter in place that is draining yellow colored urine. Doppler ultrasonography demonstrates a thrombus in the left popliteal vein. The most important next step in the management of this patient is A. daily Doppler ultrasonography of the lower extremities B. inferior vena cava filter placement C. subcutaneous heparin D. tissue plasminogen activator thrombolysis E. warfarin F. weekly ventilation/perfusion scans for a pulmonary embolus
  54. 54. Case Study       A 49-year-old man comes to clinic for follow up and monitoring of his oral anticoagulation levels. The patient is postoperative day 62 from a left total knee replacement. On postoperative day number 2 he suffered a pulmonary embolism. He was placed on intravenous unfractionated heparin and then oral warfarin. He was discharged home with follow-up instructions to return to the clinic for monitoring of his prothrombin time/international normalized ratio (INR) every 3 weeks. On return to the clinic today his PT/INR is found to be 22.4/7.3. His physical examination is unremarkable. The most appropriate management at this time is to A. admit the patient to the hospital B. instruct the patient to discontinue warfarin and return in 1 week C. instruct the patient to discontinue warfarin week until his next visit in 3 weeks D. give protamine sulfate, intravenously E. give vitamin K and follow up with the patient at his next visit
  55. 55. Thrombosis in Pregnancy
  56. 56. Preventing Thrombosis in Pregnancy Give prophylaxis with heparin during pregnancy and continued heparin or warfarin for 6 weeks postpartum in women with high risk of recurrent thrombosis:  Recent thromboembolism (within the previous 6 months)  An indication for lifelong anticoagulation  Previous thrombosis with a thrombophilia associated with a high risk of recurrent thrombosis (homozygotes for factor V Leiden, homozygotes for the prothrombin gene mutation, or antiphospholipid antibodies  A history of recurrent thromboembolism
  57. 57.   Consider heparin prophylaxis antepartum and intrapartum, and heparin or warfarin prophylaxis postpartum in women with one previous thromboembolic event even without underlying thrombophilia, family history, or other risk factors (such as obesity, smoking, recent surgery, immobilization, advanced age, and parity). Advise pregnant women, especially those with a history of thrombosis or thrombophilia, to stop smoking
  58. 58. Rxng Thrombo-embolism in Pregnancy   Avoid the use of warfarin during pregnancy because it crosses the placenta and is associated with teratogenesis and increased fetal morbidity and mortality. Treat with LMWH @ therapeutic doses.  Continue long-term prophylaxis against recurrent venous thromboembolism after the postpartum period and completion of therapy using warfarin, aiming for a target INR of 2 to 3 ( usually 6 mos if no other hx of thrombophilia is present)
  59. 59. Anemias
  60. 60. Anemias               Look At MCV  Microcytic, Macrocytic & Normocytic Iron deficiency – Colon ca scenarios, Fibroids, malabsorption syndromes (Celiac sprue), Gastric bypass surgery (Iron is mainly absorbed in the duodenum and jejunum) B12, Folic acid deficiency B12 deficiency in the elderly Sideroblastic Anemia Thalassemias Autoimmune Hemolytic Anemias – initial rx sterods, then IVIG, if unresponsive splenectomy Hereditary Spherocytosis G6PD Deficiency – sulfa, dapsone, primaquine Sickle Cell Anemia – Crisis, Aplastic crisis, Acute chest syndrome, Avascular necrosis, osteomyelitis, autospenectomy, Folate supplement importance Aplastic Anemia Anemia of Renal Disease – Give EPO if Hgb < 10 and supplement iron if Tsat < 20% Anemia of Chronic Disease Bone marrow biopsy – indications in Anemia
  61. 61. Microcytic Anemias     Importance of RDW Peripheral smear – increase in central pallor Iron studies – IRON/TIBC, Ferritin Differentiate from AOCD – in AOCD, ferritin normal/ high, iron low, tibc low
  62. 62. Rx – Iron Deficiency      Correct underlying cause – Menorrhagia, Malabsorption Recommend Hysterectomy for fibroids with menorrhagia in a patient who has completed her family. Oral Iron Supplements – preferred Side effects oral iron – nausea, constipation If too many side effects and severe Fe deficiency – consider Iron dextran IV
  63. 63. Hereditary Spherocytosis     Lack of central pallor Osmotic Fragility test Rx : blood transfusions, splenectomy Watch secondary hemochromatosis – use Desferrioxamine
  64. 64.              A 32-year-old man of Italian descent is evaluated for a routine preemployment physical examination. He has always been healthy, and his physical examination is normal. Laboratory Studies Hematocrit 35% Mean corpuscular volume 63 fL Leukocyte count 6800/μL Reticulocyte count 40,000/μL (0.7% of erythrocytes) Platelet count 270,000/μL Results of fecal occult blood testing are negative. Peripheral blood smear shows microcytosis and many target cells. Which of the following is the best diagnostic test to evaluate the cause of the anemia and microcytosis? ( A ) Coombs' direct antiglobulin test ( B ) Measurement of hemoglobin A2 level ( C ) Glucose-6-phosphate dehydrogenase screen ( D ) Measurement of serum iron, total iron-binding capacity, and ferritin levels
  65. 65.         A 22-year-old female college student of Greek descent is evaluated because she tires easily and has had palpitations when playing tennis for the past 3 months. She reports no night sweats or weight loss, and her family history is negative for anemia. She has two healthy siblings.Physical examination is unremarkable. A complete blood count shows a hemoglobin of 9.0 g/dL with a hematocrit of 28% and an erythrocyte count of 3.7 million/μL. Erythrocyte distribution width is elevated at 17% (normal range 10.5% to 14.5%). The neutrophil, lymphocyte, and platelet counts are normal. Which of the following is the most appropriate initial step in the management of this patient? ( A ) Perform hemoglobin electrophoresis for hemoglobin A2 and F. ( B ) Perform complete blood counts for siblings. ( C ) Measure serum ferritin. ( D ) Perform ultrasonography of the spleen. ( E ) Perform Southern blot analysis
  66. 66. Key Points An elevated erythrocyte distribution width is consistent with iron-deficiency anemia.  Measurement of serum ferritin can differentiate iron-deficiency anemia from the anemia of thalassemia trait. 
  67. 67. Macrocytic Anemias       Vitamin B12 def Folic acid def Alcohol/ Zidovudine Hypothyroidism Subtle clues for Vit b12 def  ataxia, neurological symps, psychosis, dementia Pernicious anemia – screen all B12 def pts with anti-parietal cell abs. ( Rx is IM b12 for life )
  68. 68. Hemolytic Anemias      Labs that suggest Hemolysis  Indirect bilirubin, LDH, Reticulocyte count, Haptoglobin Peripheral smear  help to r/o microangiopathic hemolysis (Schistocytosis), increased reticulocytes Urine Hemosiderin  elevated only in uintravascular hemolysis Direct coomb +ve  Autoimmune Hemolysis. Concomitant thrombocytopenia may suggest TTP, DIC, EVANS syndrome
  69. 69. Microangiopathic Hemolysis    Characterized by schistocytosis – fragmented RBCs on peripheral smear Seen in TTP, DIC, HUS, HELLP syndrome, CAPS, malignant hypertension Macroangiopathic hemolysis – also can have schistocytes eg: prosthetic valves.
  70. 70. Autoimmune Hemolytic Anemias        Direct coombs +ve Microspherocytes on peripheral smear Urine hemosiderin –ve LDH elevated, Hapto may be low Retic count increased Rx : Steroids, IVIG, Splenectomy Recognize Autoimmune hemolysis in CLL
  71. 71.             A 63-year-old man with stage I chronic lymphocytic leukemia (CLL) is evaluated for increasing dyspnea on exertion that has developed over the past 2 weeks. He currently takes no medications. On physical examination, he has pale conjunctivae and scattered axillary and inguinal lymphadenopathy that are unchanged from his last examination 1 year ago. His is afebrile. Pulmonary examination is normal except for tachypnea. Laboratory Studies Hematocrit 18% Leukocyte count 12,000/μL (25% polymorphonuclear leukocytes, 75%lymphocytes) Platelet count 285,000/μL A peripheral blood smear shows spherocytes, a reticulocyte count of 10%, polychromatophilia, smudge cells, and normal-appearing lymphocytes with no schistocytes. Hematocrit 1 year ago was 46%. Which of the following is the most likely cause of this new onset of anemia? ( A ) Conversion of CLL to acute lymphoblastic leukemia ( B ) Autoimmune hemolytic anemia ( C ) Disseminated intravascular coagulation ( D ) Marrow infiltration by CLL ( E ) Conversion to a large-cell lymphoma (Richter's syndrome)
  72. 72.         A 27-year-old black man is admitted to the hospital for treatment of community-acquired pneumonia, for which he received erythromycin. On the second hospital day, he is lethargic and has easy fatigability, a temperature of 38.4 °C (101.1°F), and scleral icterus. The patient had a similar episode during a childhood ear infection. His two brothers have had similar problems, though his sister has not. His hematocrit, which was 40% on admission, is now 32%. His reticulocyte count is 140,000/μL (4% of erythrocytes).Liver studies show a serum total bilirubin concentration of 5.4 mg/dL and a direct bilirubin concentration of 1.4 mg/dL. A peripheral blood smear is shown. Which of the following is the most appropriate diagnostic study at this time? ( A ) Sickling test ( B ) Glucose-6-phosphate dehydrogenase measurement ( C ) Hemoglobin electrophoresis ( D ) Erythrocyte pyruvate kinase activity measurement ( E ) No further testing
  73. 73. Key Point Following an acute hemolytic event due to glucose-6-phosphate dehydrogenase deficiency (G6PD),G6PD levels will be normal. Testing should be delayed for 3 to 4 weeks.
  74. 74. Anemias           A 19-year-old woman comes to the student health service complaining that since the new semester has begun, she finds herself unable to focus and concentrate as well as before. She attributes this largely to feeling fatigued. She denies any other symptoms such as sadness, sleeplessness, or loss of libido. She has no other medical issues. Her medications are only oral contraceptive pills. She has never been pregnant and denies current pregnancy. She has a history of long menses, often lasting 8 days. Laboratory studies show: Hct 31% MCV 69um3 Ferritin 10mcg/L The most appropriate next step is to A. administer iron, intravenously B. administer vitamin B12, intravenously C. advise her to take folate tablets D. change her oral contraceptive formulation to estrogen only E. tell her to take oral iron tablets
  75. 75.          Anemias A 5-year-old boy is brought to the clinic for a periodic health maintenance examination. He is generally healthy, enjoys school, plays well with his siblings and with other children his age. He and his family live in a housing development down the street that was built 10 years ago. Since his mother usually works until late in the evening, he tends to spend a lot of time at a friend's apartment in an old, dilapidated housing development nearby. You notice that he has unusually pale skin and mucus membranes and so you inquire about related symptoms. The mother tells you that she has noticed that he is significantly more tired than his siblings and he has been a "bit irritable" lately but she "didn't think nothing of it." He is up-to-date on all of his immunizations. There is no family history of blood disorders, however several of his playmates "are anemic." You decide to order hemoglobin, hematocrit, and a peripheral blood smear and schedule a follow-up visit in 1 week. He returns for his next appointment and you review the results of the laboratory studies. His hemoglobin is 9.5 g/dL, hematocrit is 30%, and the peripheral blood smear shows microcytic red blood cells with basophilic stippling. The most appropriate next step is to A. administer ferrous sulfate, orally B. administer dimercaprol, orally C. administer edetate disodium, orally D. determine B12 levels E. determine blood lead levels F. obtain an abdominal radiograph G. order hemoglobin electrophoresis H. Check Erythrocyte Zinc Protoporphrin levels
  76. 76.             During a routine screening for mild dementia, a 78-year-old male resident of a nursing home is found to have a low serum vitamin B12 level. He does not have fatigue, dyspnea, chest pain, dizziness, unsteadiness, or paresthesias. His medical history is significant for coronary artery disease, for which he underwent coronary stent placement 5 years ago. His medications include metoprolol and atorvastatin. Physical examination does not indicate any symptoms of vitamin B12 deficiency, such as glossitis or impaired sensation. Laboratory Studies Hematocrit 43% Mean corpuscular volume 94 fL Serum creatinine 1.4 mg/dL Serum vitamin B12 level 200 pg/mL Which of the following is the most appropriate next step in the management of this patient? ( A ) Weekly vitamin B12 injections ( B ) Intrinsic factor antibody test ( C ) Serum methylmalonic acid level ( D ) Schilling test
  77. 77. Subclinical B12 Deficiency - May not have any symps - Elevation of MMA is a sensitive marker of significant deficiency - Treat it!
  78. 78. Sickle Cell Anemia         Sickle cell trait/ Sickle cell anemia Sickling test : sickle cell screen C/F:Sickle cell crises Acute Chest syndrome Infections Dactylitis Aplastic Crises : folic acid deficiency vs. Parvo virus Avascular Necrosis hip  get MRI Labs : HGB electrophoresis, Peripheral smear – howell-jolley bodies, stress lymphocytosis, increased retic count, anemia, hemolysis, elevated indirect bilirubin Management : Acute pain crises  manage with IV Fluids, analgesics, septic w/u, electrolyte repletion, watch for substance abusers ( clues are labs) Recurrent Acute pain crises  more than 3-4 episodes per year, use Hydroxyurea. D/W pt benefits vs. toxicity of hydrea Acute Chest Syndrome  O2, analgesics, Exchange Transfusion
  79. 79.       A 17-year-old male patient with homozygous sickle cell anemia was admitted to the hospital for hydration and analgesia of a painful crisis. On hospital day 3, his condition deteriorated, with the onset of fever, new chest pain, and dyspnea. On physical examination, he has a temperature of 38.9 °C (102 °F), pulse rate of 120/min, and respiration rate of 32/min. He is using accessory muscles of inspiration and has crackles bilaterally. Chest radiographs show new, bilateral pulmonary infiltrates and a normal-sized heart. Pulse oximetry shows an oxygen saturation rate of 80% on room air. Which of the following is the most important immediate therapeutic option? ( A ) Amoxicillin ( B ) Hydroxyurea ( C ) Diuretics and digoxin ( D ) Partial-exchange transfusion ( E ) Polyvalent pneumococcal vaccine
  80. 80. Key point The acute chest syndrome is characterized by chest pain, fever, diffuse pulmonary infiltrates, and hypoxia in a patient with sickle cell anemia.  The most effective therapy for the acute chest syndrome in sickle cell anemia is partialexchange transfusion to lower the hemoglobin S. 
  81. 81. Splenectomy   Prior to splenectomy Patients should be immunized with pneumococcal, HIB and meningococcal vaccines Daily oral penicillin prophylaxis for splenectomized patients.
  82. 82.             A 56-year-old man is evaluated for fatigue during a routine office visit. His history is significant for diverticulosis,hypertension, and supraventricular tachycardia, for which he takes aspirin, metoprolol, and ramipril. On physical examination, he is afebrile, his blood pressure is 120/80 mm Hg, and pulse rate is 80/min. No abdominal tenderness,splenomegaly, or lymphadenopathy is noted. Laboratory Studies Hemoglobin 8 g/dL Mean corpuscular volume 76 fL Leukocyte count 11,200/μL Platelet count 847,000/μL Which of the following is the most appropriate next diagnostic test for this patient? ( A ) Fluorescence in situ hybridization analysis of blood for Philadelphia chromosome ( B ) Examination of bone marrow aspirate ( C ) Serum ferritin measurement and fecal occult blood testing ( D ) Repeated complete blood count in 2 weeks after discontinuation of all current medications ( E ) Bleeding-time measuremen
  83. 83. Ans. Reactive Thrombocytosis       Iron deficiency Malignancy Major Surgery Acute blood loss Primary thrombocytosis can be caused by clonal disorders, such as chronic myelogenous leukemia (CML), polycythemia vera, and essential thrombocythemia. CML is characterized by the presence of the Philadelphiachromosome in blood and marrow myeloid cells. Patients with CML typically have a high leukocyte count, high or normal platelet and erythrocyte counts, and splenomegaly. The absence of leukocytosis and splenomegaly and thepresence of severe microcytic anemia make CML unlikely Essential thrombocythemia may be associated with thrombotic and hemorrhagic complications. Patients with essential thrombocythemia have a platelet count of greater than 600,000/μL without known causes for reactive thrombocytosis; therefore, iron deficiency precludes this diagnosis.
  84. 84. Bleeding Disorders
  85. 85.       A 48-year-old female nurse is evaluated for hematuria. One week ago, she experienced dysuria, for which cephalothin was prescribed. Her history is remarkable only for an uneventful tonsillectomy as a child and removal of a benign ovarian cyst at age 36; there is no family history of bleeding. The patient does not smoke or use alcohol or recreational drugs. She has a normal diet, and her weight has been stable. She has a history of depression that has been treated with numerous antidepressants, but she is not taking any medications currently. On physical examination, she has two ecchymoses on her lower extremities. Laboratory evaluation includes a prothrombin time (PT) of 28.2 sec (INR 4.2), activated partial thromboplastin time (PTT) of 45 sec (normal < 35 sec), normal thrombin time, negative D-dimer, and normal complete blood count and platelet count. Liver enzymes are within normal limits, and serum albumin is 4.1 g/dL. An inhibitor-screen mixing study shows complete correction of the PT and PTT after mixing of patient and control plasma at a 1:1 ratio. The factor VII level is 6%, factor IX level is 10%, factor VIII level is 110%, and factor V level is 95% (reference range 60% to 150%). Which of the following is the most likely diagnosis? ( A ) Acquired factor VIII inhibitor ( B ) Lupus anticoagulant ( C ) Hemophilia B (Christmas disease) ( D ) Surreptitious warfarin ingestion
  86. 86. Key Point In severe vitamin K deficiency, the prothrombin time and the Partial thromboplastin time are prolonged. In mild vitamin K deficiency (including therapeutic warfarin), only the prothrombin time is prolonged 
  87. 87. Von Willebrands Disease
  88. 88. Screen for VWd     Screen for VWD in women with menorrhagia and no gynecologic reason for heavy bleeding, in patients with unexplained procedural bleeding, and in individuals with a personal or family history or physical evidence of mucocutaneous bleeding. Remember VWd can be asymptomatic for a long time with no hx at all and may just present with excess bleeding during surgical procedures Conduct a first-line coagulation screening work-up, including PT, PTT, CBC/platelets, and thrombin time.  If PTT is prolonged and other initial test results are normal, suspect VWD as a possible diagnosis ( BT is prolonged too. BT is N in Hemophilia ) ( Remember d/d for isolated PTT prolongation is also thrombotic condition APLA/ LA – This manifests by thrombosis though, unlike VWd which is bleeding) Initial tests for the diagnosis or exclusion of VWD include VWF function, VWF:Ag, and factor VIII activity and should be done more than once.
  89. 89. Rx - VWd   In treatment of significant bleeding events or for prevention of bleeding during invasive procedures or surgeries  use Desmopressin Remember Tachyphylaxis with desmopressin ( in case of continued bleeding after desmopressin , use Cryoprecipitate/ VWF concentrate)
  90. 90. Uremic Bleeding      Bleeding time is the best predictor for tendency to bleed. Desmopressin – Rx of choice in preventing bleeding for surgical procedures or in Rx of Bleeding Conjugated Estrogens Blood transfusion to keep hct high Recombinant Factor VIIa
  91. 91. Hemophilia Screen for hemophilia A and B in individuals with:  A history of bleeding  Family members known to have hemophilia or be hemophilia carriers  Unexplained aPTT prolongation ( BT normal)  DX : If APTT prolonged, do mixing study. Correction suggests Factor deficiency.  Then obtain quantitative factor VIII/ IX levels and activity.  In patients with prolonged PTT and decreased factor VIII activity who have no family hx of hemophilia a, obtain VWF level to r/o VWd Hemophilias can present with deep bleeding ( Hemarthrosis) apart from superficial bleeding ( mucosal bleeding, ecchymoses, bruises with minimal trauma) RX: factor VIII/ IX concentrates ( A – Factor VIII def, B – FACTOR ix DEF)
  92. 92. Thrombocytopenias
  93. 93. Thrombocytopenias       Drug Induced : HIT, GP IIb IIIA inhibitors ( abciximab, eptifibitide), Linezolid, Clopidogrel Always r/o Pseudothrombocytopenia – this is our first step. Congenital thrombocytopenia ( Some are microthrombocytopenias) Consumption Thrombocytopenias : TTP, DIC, Massive Bleeding, Sepsis ITP ITP + AIHA ( Coombs +ve, Evans syndrome)
  94. 94. Platelet transfusions - Indications     Platelets < 15k Platelets<50k + ICH/Life threatening hemorrhage Platelets > 50k  no platelets ( all we need is 50k platelets for enough clotting. So, no need of transfusions for platelets>50k) Avoid platelets in TTP/ DIC unless severe bleeding which is unlikely manifestatuion in these cases.
  95. 95. Idiopathic thrombocytopenic purpura           Previous CBC is a clue Rule out other causes – drugs, liver disease, HIV, HEP-C, APLA, SLE etc HIV related ITP responds to HAART/ Zidovudine most studied. Rx – mild ITP is often associated with a good prognosis. Platelet counts >50 × 109 cells/L with no history of bleeding  careful observation with regular visits and platelet count determinations Prednisone f Plts < 30k  If there is a response with a normalization of the platelet count over 1 to 2 weeks, taper by 5 to 10 mg/week. IVIG if immediate response is required i.e; before surgical procedures, or in initial treatment for patients with severe bleeding AND also, in patients who are refractory to treatment with glucocorticoids. Remember, response short-lived. Consider RhIG as outpatient therapy: In patients who are Rh(+) and have not had a splenectomy , For patients in whom splenectomy is not feasible and along with IVIG in patients in whom steroids have failed Splenectomy if no response to steroids (persistent platelet counts <10 × 109 cells/L for 4 to 6 weeks and for patients who have had ITP for 3 months with persistent severe thrombocytopenia (platelet count <30 × 109 cells/L) despite treatment) or Relapse after tapering Steroids Can try immunosuppressants (AZA) or Rituximab if splenectomy and Steroids are unsuccessful
  96. 96. HIT           Usually occurs with in 5-7 days after exposure to heparin. Immediate HIT is possible if there was prior exposure in past 3 months enabling circulating antibodies Heparin induced Anti-platelet Abs  screening test Serotonin Release Assay  confirmatory test Base your decision most on clinical probability rather than these tests. Features  deep vein thrombosis, PE, Arterial thrombosis in a setting of acute thrombocytopenia after exposure to heparin. Rx  Once HIT is suspected/ diagnosed , must be treated Rx  Argatroban, leperidin overlap with warfarin Lepiridin difficult to monitor Argatroban adds to INR. So, safely discontinued after warfarin started and INR of 4.0 is reached. Repeat INR in 6 hrs after discontinuing Argatroban to confirm therapeutic range INR ( 2 to 3)
  97. 97. Case Study       A 67 y/o man in previously good health is hospitalized with 2 day hx of fever and decreased consciousness. Temp is 103 F, HR 140, BP 88/50. There is no bleeding. The hgb 12.1 gm%, wbc 29,000, platelets 20,000/ul. Which of the following should be obtained next? A) Bone marrow biopsy B) Factor VIII level C) Measurement of platelet associated IgG D) Measurement of D-Dimer and fibrinogen E) Bleeding time
  98. 98. Anemias  A 21-year-old man with no significant past medical history presents to office with complaints of blood in his urine and mucosal bleeding while brushing his teeth. He denies any drug or alcohol use. He has no family history of bleeding disorders. Petechiae are noted in the oral cavity, as is dried blood in the nostrils. Laboratory studies show the following: Hematocrit 32%; white blood cell count 8,000/mm3 with 60% neutrophils; platelet count 13,000; PT 13 seconds; PTT 28 seconds; LDH 1,200 U/L; elevated indirect bilirubin. Coombs' test is positive; abdominal examination is normal; and the peripheral smear shows spherocytes. What is the most likely diagnosis? (A) Gordon's syndrome (B) Bernard-Soulier syndrome (C) Felty's syndrome (D) Thrombotic thrombocytopenic purpura (E) Evans' syndrome (F) Idiopathic thrombocytopenic purpura (ITP)
  99. 99. Myeloproliferative Disorders     Polycythemia vera ( differentiate from secondary polycythemia) Essential thrombocytosis CML Myelofibrosis ( “tear drop” cells)
  100. 100. Polycythemia Vera        Measure RBC mass to r/o relative polycythemia Differentiate from Secondary polycythemia – R/o hypoxia which is the most common cause. Presence of leucocytosis and thrombocytosis as well as spelenomegaly are big clues that this could be primary. EPO level JAK-2 mutation Pruritis during shower often seen in primary polycythemia due to histamine release from mast cells Bone marrow biopsy if EPO is low or normal in presence of polycythemia
  101. 101. Secondary Polycythemia     R/o Relative Polycythemia secondary to hemoconcentration/ dehydration  repeat CBC after Hydration Chronic Hypoxia : COPD, high altitudes, OSA, Obesity hypoventilation, intracardiac shunts, smoking  EPO elevated/ normal Neoplasms : RCC, Pheochromocytoma, Cushings disease, cerebellar hemangioblastoma, hepatoma Endocrine : Cushings disease
  102. 102.         C/F and Rx Pruritis in Polycythemia vera Ruddish complexion, erythematous rashes on abdomen, extremities, purpura. Pts have increased risk of both thrombosis and bleeding Phlebotomy to keep hct < 45% Patients with symptomatic polycythemia should undergo immediate Phlebotomy Headache, Dizziness, chestpain Blurred vision, papilledema, hypertensive emergencies are indication for immediate Phlebotomy. Begin cytoreductive therapy concomitantly with phlebotomy in cases of P.Vera (Hydroxyurea).
  103. 103. Hematological Malignancies       Leukemias – ALL, AML, CML, CLL Know when to treat CLL ( Anemia, thrombocytopenia, Rx – Fludaribine, Chlorambucil) CML – Studies, Rx AML  Know M3, associations and Rx Lymphomas  Hodgkins, NHL Secondary malignancies after radiotherapy ( Hodgkins survivors )  follow up mammograms
  104. 104. Peripheral smear
  105. 105. Ans  Plasma cell/ eccentric nucleus
  106. 106. Multiple Myeloma D/D MGUS Solitary Plasmocytoma POEMS syndrome (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes, as well as other paraneoplastic features and osteosclerotic lesions) Waldenström macroglobulinemia
  107. 107. MGUS       M-Protein < 3gm% Bone Marrow plasma cells < 10% Normal hgb, creatinine and serum calcium Normal bone survey ( x-rays not bone scan) RX : may progress to MM. There’s no evidence that chemotherapy reduces progression – so don’t treat Observation
  108. 108. Solitary plasmacytoma       Single lytic lesion in the bone No evidence of anemia, renal insufficiency or high calcium M-protein may or may not be elevated 75% progression to MM in 10 yrs No chemotherapy is recommended Rx is excision and Radiation
  109. 109. Smoldering Myeloma  Characteristics • Serum M protein >3 g/dL and/or bone marrow plasma cells ≥10% • Absence of anemia, renal failure, hypercalcemia, lytic bone lesions  Disease Management • Observation with treatment beginning at disease progression • Bisphosphonates • Supportive care • Participation in clinical trial
  110. 110. Symptomatic MM   Patients with symptomatic myeloma require immediate treatment. Characteristics • • •  Presence of serum/urine M protein > 3gm% Bone marrow plasmacytosis (usually >30%) SYMPTOMS+  Anemia, renal failure, hypercalcemia, or lytic bone lesions Treatment — Thalidomide + dexa, lenalidomide, Melphalan
  111. 111. Waldenstroms Macroglobulinemia Incidence and clinical features     Increased IgM. IgG may be decreased 1,500 cases/year in USA Median age -, 63 yrs Presenting symptoms • • • • • • Weakness and fatigue Hemorrhagic manifestations Weight loss Neurologic symptoms Visual disturbances Raynauds phenomenon 44% 44% 23% 11% 8% 3%
  112. 112. Waldenstroms Macroglobulinemia: Clinical Features  Tumor infiltration • Bone marrow • Splenomegaly • Lymphadenopathy  Circulating IgM • • • •  Hyperviscosity syndrome Cryoglobulinemia Cold agglutinin disease Bleeding disorders Tissue IgM • Neuropathy 90% 38% 30%
  113. 113. Waldenstorms macroglobulinemia     Symptoms of hyperviscocity syndrome ( Headache, chestpain, sob, blurred vision, papilledema) Rx: Plasmapheresis for circulating IgM complications Alkylating-agent based therapy (50-70% response rate) • • • •  Chlorambucil and prednisone Cyclophosphamide Melphalan CHOP (Cyclophosphomide, adriamycin, vincristine, prednisone) Nucleoside analogues (80-90% response rate) - Fludarabine - 2-Chloro-deoxyadenosine (2-CdA)
  114. 114. Hematological Emergencies      TTP LEUCOSTASIS ( CML, AML) Acute Tumor Lysis Syndrome HIT Hyperviscocity Syndrome
  115. 115. Transfusion Medicine
  116. 116. Transfusion Reactions         Febrile non hemolytic reactions Acute hemolytic transfusion reactions Delayed hemolytic transfusion reactions Anaphylactic reactions Urticarial reactions TRALI Post transfusion purpura Graft versus host disease
  117. 117. Case Study       A 43 y/o m with severe acquired aplastic anemia has not responded to immunosuppressive agents. He has a HLA identical brother who has been cleared as a donor for his planned allogeneic stem cell transplant. They are both CMV negative. Which of the following will be prevented by using irradiated cellular blood products to this patient? A) Graft versus Host disease, Transfusion related B) CMV disease C) Alloimmunization D) Hemolytic transfusion reaction E) Febrile non hemolytic transfusion reaction
  118. 118.        A 57-year-old woman (gravida 5, para 5) was admitted to the hospital with a bleeding duodenal ulcer for which she was given three units of packed erythrocytes. A regimen of antacids and cimetidine was initiated, and the patient was discharged after 3 days. Two days later, she returns to the hospital because of weakness, increased malaise, and dark urine. Her hematocrit, which was 37% at discharge, is now 26%. Liver studies show a total serum bilirubin of 6.1 mg/dL, with a direct value of 2.3 mg/dL, and a lactate dehydrogenase concentration of 467 U/L. Renal function is normal. Stools and a gastric lavage are negative for blood. The peripheral blood smear shows numerous microspherocytes. Which of the following is the most appropriate next step in the management of this patient? ( A ) Corticosteroid therapy ( B ) Blood typing re-evaluation and cross-match ( C ) Osmotic fragility test ( D ) High-dose immunoglobulin infusion ( E ) Emergency surgical consultation
  119. 119. Key points 1. A delayed hemolytic transfusion reaction occurs several dayS after transfusion and is characterized by an elevated serum lactate dehydrogenase level and a high indirect bilirubin level along with decreasing hematocrit and the presence of microspherocytes. 2. A repeated cross-match is likely to detect antibodies missed on the original cross-match.