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Discussion 3 – Case 1

Discussion 3 – Case 1.

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Discussion 3 – Case 1

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  1. Discussion 3 – Case 1 • A 60 y/o man was sent to you for pre-operative evaluation of his risk of bleeding. He is scheduled to have an elective inguinal hernia repair. He says he bleeds longer than normal after minor cuts and he has had several episodes of profuse and prolonged bleeding, but he never required a transfusion. A couple of times while playing football he got a hematoma. He does not take any medication except for an occasional aspirin. Three male members of his family on his mother's side were "bleeders" but he did not know any details. Two sisters are normal. Next slide

  2. Multitopic Case 1 Team A Discussion 3 – Case 1 • PT normal • INR normal • PTT 48 seconds 1:1 mix: Corrects • F VIII 20% • vWF:Ag 150% • vWF:RCoF 150% • Platelet aggregation studies had an abnormal release reaction consistent with impaired prostaglandin synthesis. How do you explain the coagulation defects? Discuss before next slide.

  3. Multitopic Case 1 Team A Discussion 3 – Case 1 • This is consistent with mild hemophilia A with aspirin induced platelet dysfunction. The patient’s use of aspirin made the platelet aggregation study abnormal, and his underlying, inherited Factor VIII deficiency was shown by his low Factor VIII level (20%). His past medical history and family history were consistent with the diagnosis of hemophilia A as well. Next slide

  4. Multitopic Case 1 Team A Discussion 3 – Case 1 • How is hemophilia A inherited? • What are the chances that the children of a male hemophiliac will be: hemophiliac, normal, or carriers? What are the chances that the children of a female hemophilia carrier will be: hemophiliac, normal, or carriers? Discuss before next slide.

  5. Multitopic Case 1 Team A Discussion 3 – Case 1 • Hemophilia A is a hereditary X-linked defect. With a hemophiliac male, all daughters are obligatory carriers and all sons are normal. With a female carrier, each son has a 50% chance of having hemophilia A; each daughter has a 50% chance of being a carrier. • Seventy percent of hemophiliacs will have a positive family history but 30% have de novo mutations. Next slide

  6. Multitopic Case 1 Team A Discussion 3 – Case 1 • Why does he have “mild” hemophilia whereas other people have severe hemophilia A? • How did he get to be 60 y/o and not get diagnosed with Hemophilia A? Discuss before next slide.

  7. Multitopic Case 1 Team A Discussion 3 – Case 1 • The most severe hemophiliacs have genetic abnormalities such as deletions of a part of the X chromosome; they can have Factor VIII levels less than 1%. Other mutations result in milder disease and factor VIII levels that are higher, for example 20% like this patient. • Some patients have a functionally abnormal Factor VIII and this can be seen in patients with a difference in the immunologic measurement of Factor VIII antigen, versus an assay of Factor VIII activity. • How severe do you think the hemophilia A is in his brothers? Discuss before next slide.

  8. Multitopic Case 1 Team A Discussion 3 – Case 1 • Since this is inherited as a genetic mutation, they are likely (all else being equal) to have a similar proclivity for bleeding and similar risks for surgery. What would you advise the patient about his risk of serious hemorrhage? Discuss before next slide.

  9. Multitopic Case 1 Team A Discussion 3 – Case 1 • A FVIII level of 20% is adequate for hemostasis. Spontaneous hemorrhage does not occur although there is a risk of bleeding with severe trauma or major surgery. • Family members should be screened, genetic counseling offered, and the patient should avoid aspirin. • Treatment before surgery requires infusion of recombinant Factor VIII to a plasma Factor VIII level above 80%. Next slide

  10. Discussion 3 - Case 2 A 70 y/o man was admitted with a tender, swollen, indurated left thigh; this appeared spontaneously. He also noticed some mucosal bleeding. Previously he was healthy and took no medications. He has no family history of bleeding disorders. You obtain labs. • PT 12 sec • PTT 100 sec 1:1 mix: no correction • Bleeding time 6 min (normal) • Platelet count normal Next slide

  11. Multitopic Case 1 Team B Discussion 3 - Case 2 • What is the differential diagnosis of this process? • Do you think this is an inherited disorder? • What is the relevance of the lack of PTT correction with mixing? • What other labs are you going to obtain? Discuss before next slide.

  12. Multitopic Case 1 Team B Discussion 3 - Case 2 • Factor IX normal • Factor VIII <1% • Factor VIII inhibitor 50 Bethesda units (normal = 0) Do these labs help you make the diagnosis? Discuss before next slide.

  13. Multitopic Case 1 Team B Discussion 3 - Case 2 • The lack of correction of the PTT indicates a circulating inhibitor. You can narrow down the differential diagnosis by noting that the PT was normal. Acquired Factor VIII inhibitors are the most common inhibitor of a specific coagulation factor. The Factor VIII inhibitor assay was strongly positive. Next slide

  14. Multitopic Case 1 Team B Discussion 3 - Case 2 • What population of patients is most frequently afflicted by a Factor VIII inhibitor? Discuss before next slide.

  15. Multitopic Case 1 Team B Discussion 3 - Case 2 • Unlike this patient with a spontaneous, acquired Factor VIII inhibitor, patients with inherited Hemophilia A are the most likely to develop Factor VIII inhibitors. • Factor VIII inhibitors occur in 5-20% of hemophiliacs (primarily those with severe disease). The inhibitor is an IgG antibody that inactivates Factor VIII. Next slide

  16. Multitopic Case 1 Team B Discussion 3 - Case 2 • What therapeutic options should be considered? Discuss before next slide. • IvIG • Steroids • Immune modulation

  17. Multitopic Case 1 Team B Discussion 3 - Case 2 • If control of bleeding is needed, the infusion of activated prothrombin complexes (Autoplex or FEIBA) is used to “bypass” Factor VIII. (FEIBA stands for: factor eight inhibitor bypass activity). For minor bleeding episodes, treatment is supportive and factor infusions are not given. • Use other factors. • Novo-7 = recombinant factor 7 to bypass 8 or 9 • Immunosuppressants are used to try and reduce the production of anti-Factor VIII antibody. Proceed to next slide, Case Conference!

  18. Case Conference 1: Inherited Hemophilia A vs acquired Factor VIII inhibitor Discussion 3 - Case 2 • Compare and contrast these cases: inherited Hemophilia A versus acquired Hemophilia A. Proceed to next case!

  19. Discussion 3: Case 3 • A 64-year-old alcoholic was admitted with increasing ascites due to cirrhosis. On admission the PT was 15 seconds, INR =1.55, PTT 36 seconds, fibrinogen 220 mg/dl, and platelet count 70,000. Physical exam reveals multiple ecchymoses and oozing at IV sites, nose and mouth. WBC = 10,600/mm3 and HCT = 24%. Why is the PT prolonged at admission? How would you treat this? Discuss before next slide.

  20. Multitopic Case 2 Team B Discussion 3: Case 3 • A normal PTT and a prolonged PT suggests abnormalities of Factor VII. Factor VII is the most labile clotting factor, it is Vitamin K dependent, and it is synthesized in the liver. • Treatment with Vitamin K is unlikely to be effective, as the defect is the impaired synthesis of clotting factors by the liver. • Correction of the PT is necessary only for a surgical procedure or bleeding and can be transiently improved with fresh frozen plasma. Proceed to next slide, Case Conference!

  21. Case Conference 2: DIC vscoagulopathy of liver disease Discussion 3: Case 3 • Compare and contrast these two cases: DIC and liver disease. • How can you distinguish DIC from the hematologic abnormalities associated with liver disease? • Discuss how difficult it would be to sort this out if the patient with liver disease and ascites became infected (subacute bacterial peritonitis)—that would potentially give him both causes of coagulopathy discussed in Case 2: DIC (this time from severe infection), and liver disease related coagulopathy. Discuss before next slide.

  22. Case conference 2: DIC vscoagulopathy of liver disease Discussion 3: Case 3 • DIC and liver disease, especially end stage liver failure, may be difficult to distinguish by laboratory tests. Liver disease is associated with failure of protein synthesis, decreased clearance of activated factors and fibrinolysins, thrombocytopenia and dysfunctional platelets. The PT, PTT and thrombin time (TT) are prolonged, antithrombin III decreased, fibrinogen decreased and positive FDP are seen, similar to DIC. • DIC is a manifestation of a disorder and not a disease itself. Proceed to next case!

  23. Multitopic Case 3 Team A Discussion 3: Case 3 • A 45 y/o woman comes to clinic with a rash that she has never seen before and can’t explain. It looks like tiny red dots, which started on the ankles, and then spread upward. She finds these on her abdomen as well. She is otherwise perfectly healthy, although she recalls that she has had periods in her life when she thinks she bruised a lot, and that was unexplained as well. She takes no medications at all. You look at the spots and think they are petechiae. • What labs would you order and what would you look for on physical examination?Discuss before next slide.

  24. Multitopic Case 3 Team A Discussion 3: Case 3 • A CBC is obviously the first thing to get. CBC: WBC = normal, hemoglobin = normal, MCV = normal, platelets = 8,000/mm3 (very low). • What is the differential diagnosis? Discuss before next slide.

  25. Multitopic Case 3 Team A Discussion 3: Case 3 • ITP, leukemia, collagen vascular disease, drug reaction (if she was taking one) are in the broad differential of patients with thrombocytopenia. • Since the rest of her CBC is normal, she probably doesn’t have one of the problems that can cause pancytopenia. She should not have acute leukemia either because the rest of the CBC is normal. There should be no splenomegaly on the physical examination. Next slide

  26. Multitopic Case 3 Team A Discussion 3: Case 3 • Since all the other causes of thrombocytopenia are ruled out, you conclude that this is ITP. • What are you going to do to treat it? Discuss before next slide.

  27. Multitopic Case 3 Team A Discussion 3: Case 3 • Generally, the first step to treating ITP is high-dose steroids. Proceed to Team B’s case!

  28. Multitopic Case 3 Team B Discussion 3: Case 4 • A 45 y/o woman with a history of hypertension (treated with hydrochlorothiazide), goes on a flight from Paris to San Francisco. She takes a sleeping pill, has some champagne, and doesn’t wake up for 7 hours. She is in coach. When she gets into the terminal she notices that her whole left leg is swollen and painful, making it difficult to walk. Other than the leg, she has no other symptoms. Next slide

  29. Multitopic Case 3 Team B Discussion 3: Case 4 • She is otherwise healthy. Her past medial history is only positive for a few minor surgical procedures, and while in the hospital for these she received heparin as DVT prophylaxis. She does not smoke cigarettes or take any hormones. Her family history is devoid of cancer, hematologic problems or inheritable disease. • What do you think happened and what are you going to do about it? (Hint: she’s eventually going to get heparin and something bad is going to happen to the platelets!). Discuss before next slide.

  30. Multitopic Case 3 Team B Discussion 3: Case 4 • The prolonged immobilization is a precipitating factor for a proximal DVT. You plan on starting low molecular weight heparin but her insurance company won’t allow that. You start unfractionated heparin with a goal to start Coumadin soon, after she is therapeutically anticoagulated with the heparin. Next slide

  31. Multitopic Case 3 Team B Discussion 3: Case 4 • You proceed to modify the dose, but almost two days later therapeutic anticoagulation is not achieved. As you ponder the possibility of her having anti-thrombin III deficiency, she complains of anxiety, dyspnea and pleuritic chest pain. Why did you worry about anti-thrombin III deficiency? Discuss before next slide. • Shoot for 55-70 PT • Keep adding dose and monitoring to get it there

  32. Multitopic Case 3 Team B Discussion 3: Case 4 • You worried about anti-thrombin III deficiency because heparin binds to anti-thrombin III to catalyze the inactivation of Factor Xa. Without adequate anti-thrombin III, anticoagulation with heparin is unpredictable. • Why does she have dyspnea now? Embolus. • Who are you going to call for help? Discuss before next slide. • Call surgery, TPA, interventional radiology

  33. Multitopic Case 3 Team B Discussion 3: Case 4 • She has the classic symptoms of pulmonary embolism. Who should you call for help?—your lawyer. You should have achieved therapeutic anticoagulation within the first 24 hours after admission. • Just then, the nurse tells you that the last PTT value is finally therapeutic. • Four days later, her platelet count, which was 300,000 on admission, is 80,000. The next day the platelets are 40,000. • Why do you think her platelets are low, does she have ITP? Was this due to her use of hydrochlorothiazide? Discuss before next slide.

  34. Multitopic Case 3 Team B Discussion 3: Case 4 • She has heparin induced thrombocytopenia. The other causes are much less likely, and would have been a total coincidence for them to be causing the thrombocytopenia. Explain HIT. Discuss before next slide.

  35. Multitopic Case 3 Team B Discussion 3: Case 4 • There are two kinds of HIT, a mild kind and a more severe form. This is the more severe kind denoted by substantial new thrombocytopenia. • This patient formed IgG antibodies against a complex of heparin and platelet factor 4. A subset of these patients get thrombocytopenia 5-14 days after the start of heparin. The platelets become aggregated and clot; life threatening arterial and venous thrombosis may ensue. • Different hospitals have different assays • Low molecular weight heparin is the SAME thing = heparin! • What are you going to do about it? Discuss before next slide.

  36. Discussion 3: Case 4 • Stop the heparin. • Send a serotonin release assay (a test that can detect HIT). However, in cases where you think HIT has occurred, don’t wait for the test result to take action. • The patient needs to be anticoagulated with a direct thrombin inhibitor. To block the thrombotic state, lepirudin, agatroban or a number of other anticoagulants can be used. Low molecular weight heparin is contraindicated. Proceed to next slide, Case Conference!

  37. Discussion 3: Case4 Discussion 3: Case 4 • Both patients had thrombocytopenia. Compare and contrast the causes and treatments. Next case!

  38. Discussion 3: Case 5 Discussion 3: Case 5 • An irritable, restless, infant is brought to clinic by her mother. The infant refuses to stand up, is crying, looks like she is in pain, and has not been gaining weight normally. On examination, the temperature is 100.5oF; scleral icterus is noted, the heart is hyperdynamic but not enlarged, the spleen is palpable at the costal margin and there is a spindle-shaped deformity of two fingers (and these fingers are painful). Next Slide.

  39. Discussion 3: Case 5 Discussion 3: Case 5 • CBC: WBC = 17,000/ul, RBC = 2.4 x 106/ul, HCT = 24%, Hgb = 8.0 g/dl, platelets = normal. Differential: 60% neutrophils, 40% lymphocytes; reticulocytes = 15%. Next Slide. • Reticulocyte – RBC precursor – blue dye b/c of RNA • Blue/Red cells. Will have to correct it for high number of red cells.

  40. Discussion 3: Case 5 Discussion 3: Case 5

  41. Discussion 3: Case 5 Discussion 3: Case 5 • How do you interpret the peripheral smear? • What is the diagnosis? • What other tests would you get to confirm the diagnosis? • Is this scenario consistent with hemolysis? • Is the reticulocyte count helpful? • Why is the WBC count high? Discuss before next slide.

  42. Discussion 3: Case 5 Discussion 3: Case 5 • Sickle cell anemia is most likely. • Confirm the diagnosis with a hemoglobin electrophoresis. • There is poylchromasia on the peripheral smear, a high bilirubin, and a high reticulocyte count, all features of hemolysis. • The elevated reticulocyte count of 15% indicates an appropriate marrow response. The reticulocyte count is an important test in this setting: it allows you to rule out an aplastic crisis, in which the anemia and clinical situation can more promptly deteriorate. • The high WBC is consistent with sickle cell crisis to some extent, but infection (which can instigate a sickle cell crisis) must be ruled out. Next slide.

  43. Discussion 3: Case 5 Discussion 3: Case 5 • Should you recommend genetic counseling? Discuss before next slide.

  44. Discussion 3: Case 5 Discussion 3: Case 5 • Yes. They should be told how the sickle cell gene is inherited, the difference between a heterozygote (sickle cell trait) and the homozygote. The possibility of their children inheriting both abnormal genes should be explained to the parents. End of case!

  45. Multitopic Case 6 Team A Discussion 3: Case 6 • A 30 y/o construction worker presents with recurrent severe epistaxis and spontaneous petechiae. He thinks the epistaxis and petechiae are occurring less frequently and are less severe as he gets older. He had an appendectomy at age 15 and had no bleeding problems. On exam, there are petechiae on his legs and abdomen and some gum bleeding. You are mercilessly educated on rounds: petechiae are associated with abnormalities of the vasculature, abnormal platelet function or thrombocytopenia (including primary platelet dysfunction, immune or non-immune thrombocytopenia). You order labs.

  46. Multitopic Case 6 Team A Discussion 3: Case 6 • • Platelet Count 206,000 (normal) • • PT 11 sec (normal) • • INR 0.95 (normal) • • PTT 34 sec (normal) • • BT >15 minutes (prolonged) • • F VIII 100% (normal) • • F IX 100% (normal) • • vWF:Ag 115% (normal) • • vWF:RCoF 105% (normal) • • Platelet aggregation - no response to all physiologic agents, ristocetin response normal; absence of clot retraction. • What is the diagnosis?

  47. Multitopic Case 6 Team A Discussion 3: Case 6 • Glanzmann’sThrombasthenia

  48. Multitopic Case 6 Team A Discussion 3: Case 7 • A 70 y/o male was hospitalized for a pulmonary embolism; he was treated with heparin for a week and discharged on warfarin (Coumadin). He returned to see you in clinic one month after discharge complaining of dark, tarry stools. A CBC showed a HCT of 30, whereas it was 44 upon discharge from UCDMC.

  49. Multitopic Case 6 Team A Discussion 3: Case 7 High INR ~ 1% Factor VII ~ hospitalize! • Stop coumadin until the INR gets closer to the desired range and then use a smaller dose • Low molecular weight heparin can be used too much instead of coumadin. • Fresh or frozen plasma or Vitamin K can be given to nomralize the PT and PTT rapidly if severe bleeding is occuring

  50. Multitopic Case 6 Team A Discussion 3: Case 8 • A 25 y/o man was sent to you for evaluation of thrombocytopenia (platelet count = 100,000/mm3). He has a lifelong history of easy bruising and bleeding after dental work. He has no history of surgical procedures. He does not take any medications. Physical examination revealed several large ecchymoses over his arms and legs. You get labs. Next slide • Some platelet defect, not ITP b/c it’s lifelong

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