M&M Ji Yeon Lee

Case  CC: Rectal bleeding, hematuria  HPI: 77yo Korean female with h/o HTN presented to ER with rectal bleeding and hematuria(+vaginal bleeding). She states that she noticed a little bleeding from her bottom for a week. A couple of days ago, she noticed conjunctival hemorrhage and visited an eye doctor. On the day of admission morning, she went to bathroom and passed out for a short time, and then found heavy bleeding on the floor, and brought to ER by her familly.

PMHx  HTN  Lower back pain  Abd pain in 6/06:visited ER.CT abd/pelvis neg  L knee surgery  No prior history of bleeding  No cancer screening  Medication: norvasc. No OTC meds, No herbal meds

 All: NKDA  FHx: No coagulopathy, No cancer  SHx: no cig/ETOH/drug  Lives with her son and his family at home  Immigrated from Korea 20yrs ago, has 2sons and 3dtrs.

ROS  Weakness+, no wt loss, eats small meals, no change in appetite.  No f/c  No sob. Occ chest pain+  No n/v/c/d, no abd pain  No cough/sputum  No dysuria/frequency

Physical Exam  GEN: thin, weak, elderly lady, a/o x3  VS: 67/ % RA  HEENT: pale conjunctiva and oral mucosa. No petechiae or ecchymosis  Neck: no mass  Chest: Irregular, nl S1, S2, CTAB  Abd: soft NABS, ND, mild diffuse tenderness  Ext: no edema, R lower leg bruise+

Lab findings MCV 90 Smear normal PT>140 PTT D-dimer 0.58 Fibrinogen 315 Thrombin time 15.7 Alb 3.2 Glob 2.4 Alk phos 52 AST 23 ALT 19 Tb 0.8 Ca 8.2

Hospital course  IVF for hypovolemia-BP improved.  PRBC transfusion for anemia  FFPs, factor VIIa for coagulopathy- corrected to normal PT/PTT  Cause for coagulopathy-work ups started.

Coagulation cascade

Mixing study  “weak inhibitor” aPTT (226.2) 1:1 dilution 4:1 dilution 0min hr incubation hr incubation PT (>140) 15.9

Further lab findings  Warfarin level <0.1  SPEP, UPEP nl  Coombs test neg  BCx, Ucx neg  ANA 1:160 speckled  Factor V leiden neg  Beta 2 glycoprotein neg  Lupus anticoagulant neg  cardiolipin Ab IgM 41(mod pos), IgG 7(neg)  Factor II 40%(L, )  Factor V 117%  Factor VII 676%(H)  Factor VIII 260%(H)  Factor IX 35%(L, )  Factor X 78%(L, )  Factor XI 80%

Work up  CT abd/pelvis: small renal cysts small renal cysts 1.8cm soft tissue density near hepatic flexure 1.8cm soft tissue density near hepatic flexure wall thickening in rectosigmoid colon wall thickening in rectosigmoid colon  Colonoscopy: 4mm sessile polyp in ascending colon 4mm sessile polyp in ascending colon blood clot in area of splenic flexure blood clot in area of splenic flexure -->Bx: ulcer-->Bx: ulcer

Diagnosis  Suspected prothrombin inhibitor

Hospital course  No more bleeding. Stable H/H  No response to PO vitamin K  Continuous needs for FFPs  Treatment started with cyclophosphamide 100mg qd, prednisone 40mg qd, and rituximab qwk.  No improvement over 1 month period

 Ethical issues How long should we wait to see the effectiveness of treatment? How long should we wait to see the effectiveness of treatment? Futility? Futility? Withdrawal of care? Withdrawal of care?

Prothrombin inhibitors  Most often detected in pts with antiphospholipid antibodies.  Can cause significant clinical bleeding  Bind to a nonactive portion of the molecule, resulting in accelerated clearance of prothrombin  Lab testing is most consistent with a factor deficiency rather than an inhibitor since the functional activity of prothrombin is not impaired  Specific immunochemical measurement of the prothrombin concentration is required to establish the diagnosis.

Treatment  Control of active bleeding: prothrombin complex concentrates prothrombin complex concentrates recombinant human factor VIIa recombinant human factor VIIa Based upon the severity of bleeding and the titer of the inhibitor Based upon the severity of bleeding and the titer of the inhibitor If no response: extracorporeal plasmapheresis with an immunoadsorption column to absorb the autoantibody can be tried. If no response: extracorporeal plasmapheresis with an immunoadsorption column to absorb the autoantibody can be tried. The suggested dose of FFP is 15 to 20 ml/kg, with a target prothrombin level >30 percent The suggested dose of FFP is 15 to 20 ml/kg, with a target prothrombin level >30 percent  Eliminating the inhibitor: Prednisone and cyclophosphomide: Prednisone and cyclophosphomide: IVIG –not recommended as inintial therapy IVIG –not recommended as inintial therapy Cyclosporine if resistant to all of the above Cyclosporine if resistant to all of the above Rituximab alone or with cyclophosphamide Rituximab alone or with cyclophosphamide Cladribine: purine analog Cladribine: purine analog