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Heme talk 10 29-15- dr james

Heme talk 10 29-15- dr james

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Heme talk 10 29-15- dr james

  1. 1. Approach to delayed post traumatic bleeding in a patient with recently Dx myeloma • Discussion of a patient with development of large gluteal hematoma ~ 1 week s/p BM Bx; heme was consulted regarding late traumatic bleeding and myeloma (possible connection?) • Initial work up and differential diagnosis for delayed post- traumatic bleeding • Specific emphasis on possible bleeding diatheses a/w myeloma • Special testing and workup if initial testing is negative • Discussion of possible etiology of bleeding in this patient and disease management
  2. 2. Case Presentation • 49 year old man with no prior major bleeding history diagnosed with IgA lambda multiple myeloma 8/2015 who subsequently developed a large gluteal hematoma requiring a reported 5U PRBC 8 days following bone marrow biopsy • Developed DOE 2/2015; self reported Hx of thalassemia; patient was concerned about anemia and eventually presented to PCP in 7/2015; was reportedly anemic • Protein was elevated at 8.8 and PCP sent SPEP: IgA lambda paraprotein at 3.51 g/dL • Serum IgA level was 3426 mg/dL (70 – 400), IgM undetectable (40 – 230), IgG 169 (700 – 1600) • Referred for BM Bx performed on 8/5; 80% clonal plasma cells reported; no immediate complications from BM Bx
  3. 3. Case Presentation • CT chest was obtained for dyspnea and tachycardia (8/4/15); demonstrated idiopathic pulmonary nodules. No PE.
  4. 4. Case Presentation • On 8/13 he developed lancinating pain down the right lower extremity originating from the right buttocks; felt a mass and noted increased dyspnea; presented to outside hospital on 8/14 • MRI demonstrated intramuscular gluteal hematoma measuring 20 x 8 x 12 cm • Hgb had dropped to 6.5 g/dL • Received a reported 5U PRBC and was discharged on 8/25; no clear etiology identified; reportedly normal PLT, PT/INR
  5. 5. Case Presentation • Established care at MSKCC on 8/26; continued to have a painful large palpable hematoma at that time and ongoing dyspnea; was admitted for expedited workup • Hematology was consulted regarding possible platelet dysfunction or other acquired bleeding diathesis in setting of IgA paraproteinemia given late bleeding event following reportedly uncomplicated BM Bx
  6. 6. Case Presentation • Review of systems • Ongoing dyspnea on exertion • Patient thinks he has been gaining weight, notices swelling of legs • Reported intermittent pain at the site of his hematoma; interfered with ambulation at times • Ongoing paresthesias and pain radiating from right buttock to posterior calf • No rashes • No mucosal bleeding, hematuria, hematochezia, melena • PMH: • wisdom tooth extraction as a teenager, but did not experience prolonged bleeding • no past history of bleeding problems or thromboses • Possible thalassemia trait • HTN
  7. 7. Case Presentation • Family History • No family history of bleeding disorders • Father with reported history of thalassemia • Exam: • No oral lesions • No rashes/petechiae • Lungs clear, no murmurs • Notable for large palpable gluteal mass • Mild LE edema • Strength in bilateral LE intact
  8. 8. Case Presentation: Initial synopsis • 48 year old man with recently Dx IgA multiple myeloma based on paraprotein and BM involvement with clonal plasma cells with no personal or family history abnormal bleeding presenting with large non- resolving gluteal hematoma developing ~1 week following uncomplicated BM Bx • Where to start? • Do the findings suggest a bleeding disorder? And if so is this consistent with an acquired on inherited disorder? • Could the IgA multiple myeloma predispose to him to bleeding?
  9. 9. Initial work up in suspected bleeding diathesis
  10. 10. Relevant historical information: questions to ask • Elicit history of past bleeding problems: • history of iron-responsive anemia • bleeding outcomes following surgical procedures and tooth extractions • history of transfusion • character of menses • dietary habits or antibiotic use which might predispose to vitamin K deficiency • Elicit h/o thyroid and liver (synthetic dysfunction) and kidney disease (platelet dysfunction) • Complaints such as hematuria, melena, and menorrhagia less helpful: structural causes are more commonly responsible • History of surgical procedures or tooth extractions or significant injury without abnormal bleeding suggests against inherited hemorrhagic disorder
  11. 11. Relevant historical information: questions to ask • Family history of bleeding • negative family history does not exclude an inherited coagulation disorder • E.g. up to 30 to 40 percent of patients with hemophilia A have a negative family history
  12. 12. Relevant historical information: questions to ask • Family history of bleeding • negative family history does not exclude an inherited coagulation disorder • E.g. up to 30 to 40 percent of patients with hemophilia A have a negative family history • Medications • Aspirin, NSAIDs, thienopyridines, warfarin, NOACs • Significantly increased bleeding risk in patients taking two of these classes • Clinical features • (table)
  13. 13. Differential Diagnosis • Platelets (qualitative/quantitative) vs. coagulation pathway (qualitative/quantitative) vs. structural (vessel disorder; amyloidosis) • Acquired vs. inherited Platelet Disorder Acquired • Thrombocytopenia • Uremia • Liver disease • Paraproteinemia/dysproteinemia • Acquired von Willebrand disease • MGUS, myeloma Platelet Disorder Inherited • Von Willebrand disease (prevalence estimated 1%) • Bernard-Soulier syndrome • Glanzmann thrombasthenia • Storage pool diseases
  14. 14. Differential Diagnosis • Multiple myeloma or Waldenstrom macroglobulinemia patients may have platelet dysfunction • Paraproteins can affect platelet adherence, activation, aggregation, and procoagulant activity • Majority of bleeding complications are due to the effects of hyperviscosity • Paraprotein against GPIIIa described in a patient with multiple myeloma and acquired thrombasthenia (J Clin Invest. 1986;77(1):157.) • Study of 40 patients with MM found ristocetin-induced platelet aggregation (RIPA) abnormalities in 6 (15%) • all six of them had normal levels of von Willebrand factor antigen • RIPA was significantly decreased in healthy donors in the presence of paraprotein (P<0·001) • (Hematology. 2011 Jul;16(4):209-12)
  15. 15. Differential Diagnosis • Depletion of high MW vWF multimers in MGUS patients • Blood. 2011 Jun 23;117(25):6777-85
  16. 16. Differential Diagnosis
  17. 17. Differential Diagnosis • Platelets (qualitative/quantitative) vs. coagulation pathway (qualitative/quantitative) vs. structural (vessel disorder; amyloidosis) • Acquired vs. inherited Coagulation Disorder Acquired • Liver disease • Consumptive coagulopathy • Hyperfibrinolysis (amyloid, myeloma) • Paraproteinemia/dysproteinemia • Amyloidosis (Factor X deficiency) • Acquired factor inhibitor to intrinsic/extrinsic cascade proteins • Anti-plasmin inhibitor (amyloidosis) • Fibrinogen antibodies/inhibitors (reported in myeloma) Coagulation Disorder Inherited • Relatively more common • VIII (1/5000 male births) • IX (1/20,000 male births) • Rare • XIII, X, VII, V, and II (1 in 500,000 to 1 in 2,000,000) • Dysfibrinogenemia • alpha-2 antiplasmin deficiency, plasminogen activator inhibitor-1 deficiency Vascular purpuras • HHT • small vessel vasculitis • purpura associated with the presence of paraproteins
  18. 18. Initial workup prior to consult • Hemoglobin 8.5, WBC 15.3 (12.4 neutrophils), Platelets 314 • Blood type O+ • INR 1.2 (0.8 – 1.2), PTT 30.3 (25 – 38) • T bili 1.9, Protein 8.5, Albumin 3.4, AlkPhos 269, ALT 70 • Ca 9.5, Cr 0.8 • LDH was 275 • Beta-2 microglobulin was elevated at 4.0 • Ferritin 469, TSH 2.6, Iron 19, Transferrin saturation 7% • Peripheral blood smear: • 1+ teardrops with an MCV of 78 • no schistocytes • BNP was elevated at 2320 and troponin was 0.21
  19. 19. Interpretation of initial labs • Thrombin time 20.4 (17 – 24) • Fibrinogen 243 (190 – 387) • Hemoglobin 8.5, WBC 15.3 (12.4 neutrophils), Platelets 314 • INR 1.2, PTT 30.3
  20. 20. Interpretation of initial labs • Next step in bleeding diathesis workup? • Why is the BNP elevated? • Dyspnea on exertion out of proportion to anemia?
  21. 21. Workup Continued • MRI 8/27 at MSKCC - hematoma with approximately 1 L of fluid present • TTE was performed demonstrating mild to moderate mitral regurgitation and possible left ventricular hypertrophy with ejection fraction 57%
  22. 22. Workup Continued • Fat pad Bx obtained 8/28 - Positive for amyloid within vessels, electron microscopy demonstrated fibrils arranged in random, rigid with a solid cross section, ranging from 8-12 nm in diameter diagnostic of amyloid deposits
  23. 23. Workup Continued • Cardiac MRI 8/31/15 – EF 50 %, mild concentric hypertrophy, diffuse myocardial enhancement involving all left ventricular wall c/w amyloid deposition • Pulmonary nodules seen on CT may represent amyloid deposits (amyloidomas)
  24. 24. Ongoing workup • von Willebrand disease testing: • Ristocetin cofactor assay: 150 (normal) • vWF:Immunoactivity 234 (50 – 150%) • Factor VIII activity can also be obtained • Platelet function testing Platelet ATP secretion (Lumi-aggregometry) • ADP, Epi, Arachidonic acid, Collagen, Thrombin all were WNL • Platelet aggregation study (PFA-100?) • (all normal) • ADP (high, int, low) • Epi, AA, Collagen, Ristocetin
  25. 25. Ongoing workup • Clotting factor deficiencies? • Factor X - 71% (50 – 150%) • Factor XIII antigen • 19% (68 – 159%), repeat level 28% • Factor XIII activity (send out) • 45% (60 – 150%) • Factor XII 85% (50 – 150%)
  26. 26. Factor XIII • Tetrameric protein A2B2 – half life 9 – 14 days • A subunit contains the active site – mediates fibrin cross-linking • Synthesized by hepatocytes, monocytes, megakaryocytes • B subunit • Synthesized by hepatocytes and combines with A subunit in serum • Requires activation by thrombin (cleavage of inhibitory peptide)
  27. 27. Factor XIII http://academic.mu.edu/bisc/siebenlistk/research.html
  28. 28. Factor XIII - deficiency • Congenital Factor XIII deficiency is autosomal recessively inherited • Most common deficiency: FXIII A subunit; incidence ~ 1 in 2 million • Typical bleeding manifestations in severe disease • umbilical stump bleeding • postoperative bleeding • intracranial hemorrhage (more common than with other factor deficiencies) • recurrent pregnancy losses • delayed wound healing • Muscle and subcutaneous hematomas • Factor XIII deficiency severity: • Severe: level < 5% • Moderate: between 5% and 10% • Mild: levels > 10%
  29. 29. Factor XIII - deficiency • Acquired Factor XIII deficiency • Major surgery, pulmonary embolism, stroke, leukemia, myelodysplastic syndrome, Crohn disease, ulcerative colitis, Henoch-Schonlein purpura, cirrhosis, sepsis, and disseminated intravascular coagulation • FXIII-A subunit levels drop to 20% to 70%, caused by decreased synthesis or increased consumption • rarely requires replacement therapy • Auto-antibodies have been described that inhibit FXIII or decrease serum levels
  30. 30. Factor XIII - testing • Clot solubility testing • Urea method – tests for clot dissolution in 5M urea • MCA – similar clot lysis testing • ELISA for FXIII – tests total antigen level • Functional FXIII Assays – tests transglutamidase activity of XIIIa; • substrate release of ammonia • Chromogenic FXIII Assays • Activity reported as 0 - >250%
  31. 31. Factor XIII - deficiency • Treatment of severe FXIII deficiency • Goal to raise FXIII level to > 5%; usually results in hemostasis; may require higher levels • Rx options: • Recombinant factor XIII A subunit (Tretten) – 35 international units/kg • Factor XIII concentrate: Corifact – 40 international units/kg; Fibrogammin, Fibrogammin P – 10 to 20 international units/kg • FFP (solvent/detergent [S/D] treated if available) – 2 to 3 mL/kg • Cryoprecipiate – 1 bag/10 kg
  32. 32. Factor XIII - deficiency • Long half live  infrequent dosing requirements for maintenance (e.g. weekly) • Prior to surgery, if dose given within 7 days, repeat dosing may not be necessary • Pregnancy • administration of factor XIII must begin by five weeks gestational age in patients receiving factor XIII to prevent miscarriage • Goal activity > 10% • Prophylaxis • Indicated in patients with FXIII activity < 5% (severe) • If subunit B deficient, cannot use rFXIII-A (Tretten) • Efficacy of PPX (Tretten) single arm phase III (41 pts) • ABR 0.048, versus 0.33 for other prophylactic therapy or 2.91 for on-demand therapy • 37 with no bleeding that required therapy (90 percent) • Five bleeds in four patients (trauma-related) required therapy • 48 bleeds did not require therapy
  33. 33. Factor XIII - deficiency • The concentration of subunit A in plasma is 0.60-1.30 U/mL and that of subunit B is also is 0.60-1.30 U/mL U/dL. Much of FXIII circulates in blood in association with fibrinogen. Blood. 2012;119(22): 5111-5117
  34. 34. Follow up course • Started CyBorD 8/31/15; diuresed and lost 8 kg • After cycle 4, achieved VGPR with M-spike 3.51  0.29 g/dL • Developed NSVT (LifeVest defibrillator), Atrial fibrillation; started on rivaroxaban and amiodarone in 9/2015 • Admitted for BRPBR 10/2015; self limited, a/w constipation r/t velcade • No additional bleeding problems – remains on rivaroxaban • Overall was felt to have a mild Factor XIII deficiency leading to a possibly increased bleeding risk with trauma; unclear if inherited vs. acquired • Unclear if component of amyloid angiopathy was present

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