7-26-2005 Clinical Pathology Conference: to plasmapheresis or not

1. 7-26-2005 Clinical Pathology Conference: to plasmapheresis or not? Bill Zaloga, DO

2. Chief Complaint Presented to an outside hospital with progressive fatigue and weakness 1 week prior to transfer to MCG. Found with “malignant hypertension”, severe anemia (Hgb 4-6 g/dL), acute renal failure with Cr 3; increased retics and LDH, and decreased haptoglobin.

3. History of Present Illness 41 year old African-American male whose creatinine has been slowly increasing with decreasing hemoglobin which resulted in admission to the Eisenhower Medical Center MICU 6/23/2005 with a hypertensive emergency. Progressive fatigue & weakness x 1 month, SOB with exertion. His “malignant htn” was brought under control, and although he had some drop in his platelets he never had thrombocytopenia. Dx HUS due to Gemzar treatment for adenocarcinoma. 7/1/2005 He was transfered from the outside medical center after no response to transfusion, and steroids. Plasmapheresis could not be done there so transfer to MCG.

4. Past Medical History No prior Hx of htn, and with a nl baseline creatinine. H/O chronic L. cephalic v. thrombosis, on lifelong coumadin. H/O head & neck squamous ca with brain mets dx 1997 (rad neck diss). Craniotomy, gamma knife 1998. 1998 treated with dilantin with ensuing ARF that required temporary dialysis. Nov. 2004, presented with pancoast tumor (adenoca) and small bowel adenoca (resection). Dx of metastatic adenoca of unknown primary. The pancoast tumor was treated with 4 cycles of carboplatin/taxol which failed, so Gemzar (Gemcitabine) started Jan. 2005, and he got 6 doses (last dose early June 14, 2005). No gemzar 6-21-2005, but got 2 U PRBCs for anemia.

5. Medications/Family History/Social History Oldest brother and father with hypertension. Smokes 2 ppd x 20 yrs. Retired from the army.

6. MCG admit physical exam T 36.8, RR 18, HR 72, BP 116/65. Alert, oriented, NAD. No scleral icterus. No peripheral edema. No hepatosplenomegaly. Nail bed pallor.

7. MCG laboratory findings 7/1/2005 H/H = 8.5/24, plt 215K, retic 3.6%, T.bili 0.8, LDH 951, BUN/Cr = 68/6.7, haptoglobin < 6 mg/dL. O pos/Ab scrn neg. aPTT 35.5, PT 12.9. MCV 90.6, MCHC 34.9 Peripheral smear: mod. Schistocytes (all smears had sl-mod schistos with the last with sl schistos). Plt nadir 46K on 7-9-2005 then steady increase to 240K at D/C 7-21-2005. LDH highest (951) 7-1-2005,fluctuated,435 on D/C. BUN/Cr fluctuated but slight increase at D/C, 43/9.2 Highest T. bili was 1.3. Haptoglobin stayed low. VMA, normetanephrines, metanephrines = low-nl. ANA neg. vit. B12 nl.

8. MCG laboratory findings 7/19/2005, kidney biopsy Thrombotic microangiopathy, severe with mod-severe acute tubular injury, and mild-mod diffuse interstitial fibrosis (no platelet-fibrin thrombi, capillary loops empty), arterioles are obstructed by swollen endothelial cells with focal fibrinoid necrosis and mucoid intimal change, tortuous vessels suggest background htn). Cause: HUS (gemzar)? Malig htn? Other?

9. Our pts. Renal biopsy, H & E

10. Initial impression Not a straighforward case of HUS (no thrombocytopenia). The history of “malignant htn” brings a MAHA component into DDX. Not an ongoing hemolysis since bili not elevated, and discrepant with LDH of 950 (from tumor?).

11. MCG hospital Course 7-1-2005 Prednisone, heparin protocol. Femoral catheter placed at outside hospital. Daily plasmapheresis initiated 7-1-2005 with type compatible FFP replacement. Nephrology consult with daily dialysis started. Blood pressure control. 7-4-2005, 2 U PRBCs. 7-8-2005 1 U PRBCs. 7-5-2005, platelets begin to decline (plasmapheresis #5). 7-9-2005, Plt 46K, heparin discontinued (HIT abs neg), Argatroban started (stopped 7-14-2005). 7-9-2005, blood pressure 250/130 and reportedly labile since pt been here, plasmapheresis held (reminded hem-onc that protein bound meds removed by plasmapheresis and to dose drugs after, with better control afterwards).

12. MCG hospital Course 7-10-2005 plt 67K, plasmapheresis #8 7-11-2005 plt 80K, plasmapheresis #9 (last one, suspect MAHA due to malig htn). BP nl, H/H stable (10/28.3), BUN/ Cr = 65/7.3, LDH 541. 7-15-2005 Htn normalized, hgb stable, plt 103K, prednisone taper, 2 U PRBCs. Spiked fever, MSSA in blood & catheter & urine. Femoral line removed & IV abx started. 7-19-2005 Right tunnel HD catheter placed for continued intravenous abx and dialysis for ESRD (renal consult: recovery unlikely). D/C 7-21-2005 with normalized vital signs (htn controlled with medication), stable anemia (hgb 8.1), and neg blood cultures, for home care abx therapy. Transfused with 2 U PRBCs without problems.

13. DDX: Normochromic Normocytic Anemia routine data Anemia due to hemolysis or bleeding has a normal or slightly elevated MCV and an appropriate reticulocyte index. Anemia with a normal MCV and a low retic index DDX: renal failure, anemia of inflammation/malig., early iron def., combined iron def.+megalobl. anemia, sideroblastic anemia, myelophthisis, and bleeding or hemolysis plus one of the previous.

14. Anemia of renal failure Unusual with creatinine less than 3. Hct is variable, even in severe renal failure, from the low teens to the mid-30s. Decreased marrow erythropoiesis due to decreased erythropoietin or uremic toxins. Smear may show burr cells, and an occasional “microangiopathic” smear. Mild thrombocytopenia, 90-140K, in severe renal insufficiency.

15. DDX: Normochromic Normocytic Anemia Blood loss: no signs in this patient.

16. DDX: Normochromic Normocytic Anemia Hemolysis An the absence of bleeding with a normocytic anemia and increased reticulocytosis suggests hemolysis. Intravascular Hemoglobinemia, hemoglobinuria, hypohaptoglobinemia, hemisiderinuria. Elevated LDH, but nonspecific. Seen in microangiopathic hemolysis, burns, AHTR ...

17. DDX: Normochromic Normocytic Anemia Extravascular Hemolysis Most hemolytic events aren’t intravascular. No hemoglobinemia, hemoglobinuria, or hemosiderinuria. Haptoglobin only partly saturated. Maybe indirect hyperbilirubinemia (direct in biliary obstruction or liver disease, and indirect in hemolytic anemia when other liver function tests normal) Often only presumptive evidence. Seen in immune hemolysis, DHTR, hemoglobinopathies, hypersplenism ...

18. DDX: Normochromic Normocytic Anemia Anemia of chronic disease: One of the most common mechanisms. Any chronic, or acute inflammatory state. Similar mechanism in cancer patients. Mech: decreased rbc survival, decreased erythropoietic activity, and abnormal iron kinetics.

19. DDX: Normochromic Normocytic Anemia Reduced marrow production. This patient had a low reticulocyte index, about 2%, on admit. Normal retic count with normal Hct is 1%. Marrow can triple its rbc production almost immediately in response to acute blood loss or hemolysis. To correct retic count for anemia: Retic index = retic% X pt. Hct/nl. Hct. Retic index is least 3% is an appropriate marrow response to anemia.

20. DDX: Normochromic Normocytic Anemia Peripheral smear help Can check for marrow response. Red cells may suggest etiology. Spherocytes: in large numbers may be immune hemolysis, hereditary spherocytosis, hemoglobin C hemoglobinopathy. Hereditary elliptocytosis. Schistocytes: in microangiopathic states if >1% rbc in right clinical setting (schistos common in renal dz but usually <1%). Mech: lesions produce high shear forces, or produce inflammation that make fibrin strands. Coomb’s test Done when immune hemolysis is suspected.

21. DDX hemolysis with fragmented red cells on the peripheral smear Macrovascular hemolysis (mechanical disruption). MAHA (TTP, HUS, DIC, malignant htn, vasculitis, disseminated carcinomatosis, vascular malformations). HELLP syndrome Rx deliver fetus. If accompanied by significant thrombocytopenia think of: DIC, HUS, TTP…(A destructive thrombocytopenia will show ample marrow megas and large platelets in smear). Treat all fragmentation hemolysis by Rx of underlying mech.

22. Thrombocytopenia DDX Routine data: plt count, H&P, smear, +/- marrow exam Decreased survival/consumption, sequestration (large plt on smear, inc. megas). Thrombotic microangiopathy (isolated platelet consumption due to endothelial injury or increased plt activation) TTP/HUS. Intravascular activation of coagulation cascade by malignant hypertension, sepsis, shock, toxin exposure, malignancy DIC. Immune thrombocytopenia (if severe, <10K). Hypersplenism (anemia not usually significant), abnormal vessels, prostheses. Decreased production (small plt on smear, dec. megas). Myelophthisis (if severe, <10K, maybe acute leukemia). Primary marrow disorders (if severe, <10K, maybe aplastic anem). Infection. Marrow depressant drugs. Ineffective production (variable plt size, nl or inc. megas). Megaloblastic process.

23. Septicemia Infection may decrease platelet production. Endotoxin will cause platelet capillary sequestration.

24. DIC In acute DIC, thrombocytopenia is essentially always present and often the first symptom. Marrow may compensate if the DIC is chronic, and coag factors may be low or normal. Best clinical example of chronic DIC is metastatic usually adenoca hypercoagulable phenomena including migrating thrombophlebitis with platelet rich microthrombi (Trousseau’s syndrome mechs include tumor expressing tissue factor and tumor procoagulant). Trousseau’s Rx is to treat tumor. Often precedes cancer dx. Intravascular clotting may be initiated by release or increase of thromboplastic substances into circulation in malignancy and tissue ischemia for example. Lab: clotting factors consumed (low fibrinogen and increased D-dimer, distinguishes it from TTP/HUS) platelets consumed, fibrinolysis activated. PT, PTT, TT, abnormal with rbc fragments (schistocytes and spherocytes). Widespread intravascular coagulation and bleeding.

25. DDX immune thrombocytopenia Primary (ITP/autoimmune thrombocytopenic purpura) Viral or bacterial infection Collagen vascular diseases Lymphoproliferative disorders Immunodeficiency Drugs (to treat just stop the drug) Heparin Dilantin Lasix Others

26. Thrombotic microangiopathy Direct platelet consumption triggered by endothelial injury and platelet aggregation VS. direct activation of coag pathway in DIC. Thrombosis of capillaries and arterioles. Most thrombi are mostly platelets and scant fibrin. Norm coag levels with little prolongation of PT or aPTT. MAHA. Thrombocytopenia. Sometimes renal failure with platelet or platelet-fibrin thrombi in renal arteries or glomeruli and necrosis of vessel walls. Classic childhood HUS: assoc intestinal infection (O157:H7 verocytotoxin producing E. coli). Adult HUS: assoc infection, antiphospholipid abs, preg. compl., metastatic carcinoma, chemo, immunosuppression, vascular renal disease such as scleroderma and htn, and idiopathic...) Thrombocytopenia, MAHA, and renal failure also seen in vasculitis (but usually other Sxs too), and malig htn (hx uncontrolled htn w/ diastolic > 130).