7262005 Clinical Pathology Conference: to plasmapheresis or not

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

• Bill Zaloga, DO

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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.

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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.

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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.

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Medications/Family History/Social History

• Oldest brother and father with hypertension.
• Smokes 2 ppd x 20 yrs.
• Retired from the army.

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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.

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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 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.

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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?

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Our pts. Renal biopsy, H E
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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?).

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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).

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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.

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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.

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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.

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DDX Normochromic Normocytic Anemia

• Blood loss no signs in this patient.

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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
  ...

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DDX Normochromic Normocytic Anemia

• Extravascular Hemolysis
• Most hemolytic events arent 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 ...

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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.

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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.

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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
• Mech lesions produce high shear forces, or
  produce inflammation that make fibrin strands.
• Coombs test
• Done when immune hemolysis is suspected.

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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.

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Thrombocytopenia DDX

• Routine data plt count, HP, 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,
• Hypersplenism (anemia not usually significant),
  abnormal vessels, prostheses.
• Decreased production (small plt on smear, dec.
  megas).
• Myelophthisis (if severe, leukemia).
• Primary marrow disorders (if severe, aplastic anem).
• Infection.
• Marrow depressant drugs.
• Ineffective production (variable plt size, nl or
  inc. megas).
• Megaloblastic process.

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Septicemia

• Infection may decrease platelet production.
• Endotoxin will cause platelet capillary
  sequestration.

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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
  (Trousseaus syndrome mechs include tumor
  expressing tissue factor and tumor procoagulant).
  Trousseaus 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.

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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

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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
  (O157H7 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).

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TTP/HUS

• Rare.
• Marked platelet consumption accelerated by
  platelet-fibrin thrombi leads to microangiopathic
  hemolysis with schistocytes.
• Dx usually clinical and lab (/- renal bx).
• Classic TTP pentad fever, thrombocytopenia,
  MAHA, transient neurologic symptoms, and renal
  failure.
• Renal failure prominent in HUS (with assoc MAHA
  and thrombocytopenia).
• Only MAHA and thrombocytopenia needed to DX TTP.
• TTP usually adults spares kidneys. TTP/HUS
  adults usually idiopathic.
• HUS usually kids with kidneys Sxs prominent and
  absence of neuro. Sxs. Abx may increase toxin
  release and HUS.
• TTP/HUS difference is the location of thrombi.

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TTP/HUS

• Lab notably, PT and PTT normal or sl inc.
• Platelet, fibrin aggregates in the arterioles and
  capillaries with thickened walls, endothelial
  swelling and proliferation, fibrin deposits in
  lumen, arteriole fibrinoid necrosis, intimal
  hyperplasia. Morphology similar to malig htn (/-
  htn).
• Smear has schistocytes, reticulocytosis, usually
  severe thrombocytopenia.
• LDH and bilirubin elevated.
• Coombs neg.
• DIC may occur as renal failure ensues.

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TTP/HUS

• Cause
• Deficiency or antibodies of vWF cleaving
  protease, ADAMTS-13 gene, or endothelial injury.
• Protease normally cleaves large vWF multimer into
  smaller multimers in the blood.
• vWF normally unfolds in circulation when it binds
  to damaged endothelium, or when the shear stress
  is increased in arterioles and capillaries.
• Unfolded vWF is them cleaved by the protease.
• When protease is deficient, the vWF multimers
  unfold in the arterioles and capillaries and
  induce direct plt aggregation and microvascular
  thrombi which fragment rbcs.
• No approved test for the protease yet.

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TTP/HUS

• ADAMT-13 protease deficiency can be congenital or
  acquired.
• Congenital chronic, relapsing TTP.
• Acquired
• Trigger infection, drugs (Gemcitabine (Gemzar),
  Mitomycin, Cisplatin, Bleomycin, Ticlopidine),
  immune system abnormalities (SLE, HIV).
• Chemotherapeutic agents also lead to
  myelosuppression.
• Leads to IgG autoimmune reaction to ADAMTS-13
  protease.
• Reaction usually transient and a single episode.

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TTP/HUS

• Management Goals
• May be irreversible (mortality today
• Replace ADAMTS-13 protease.
• Remove the antibodies.
• Plasma Exchange does both (first line Rx for
  TTP).
• FFP infusion can be used.
• But the Abs remain in the blood.
• Not as effective as plasma exchange.
• Can be used for congenital deficiency of
  ADAMTS-13 protease.
• Plasma exchange
• Start early. Usually about 9 procedures (5-80
  reported).
• For TTP, do daily until platelets increase and
  LDH to normal for 2-3 days. Too soon and may
  relapse.
• Malig assoc TMA shows mod or transient
  improvement, so Rx is reduce tumor burnden.

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TTP/HUS

• In adult HUS ARF is usually more severe,
  plasmapheresis is not as successful, but because
  of overlap with TTP, plasmapheresis ASAP.
• Hemodialysis is used to manage many child HUS
  pts, and most patients recover in a few weeks.
  If mild only fluid electrolyte mgmnt necessary.
• Plasmapheresis for HUS is performed until plt inc
  and renal improves.
• Immunosuppression
• Some success (steroids, rituxan, vincristine).
• Platelet transfusion
• Contraindicated
• Exacerbates platelet thrombi formation
• Patients generally dont bleed so use only in
  life threatening hemorrhage.

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TTP/HUS

• Fibrin stain.
• Platelet-fibrin thrombi (red) in glomerular
  capillaries.

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Hypertensive emergencies

• Diastolic pressure 120-140 is severe and should
  be acutely reduced.
• Initial concern is identification of end-organ
  damage.
• CNS, cardiopulmonary, renal
• Secondary htn emergencies to treat
• CNS vascular event, renal failure,
  pheochromocytoma, renal artery stenosis.
• Occasionally malig htn presents as MAHA, renal
  insuff, and thrombocytopenia. Mech is endothelial
  injury, fibrin strands from and shear rbcs, trap
  plts.

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Hypertensive emergencies

• Lab
• Cardinal sign of acute hypertensive nephropathy
  is unrecognized elevation or serum creatinine in
  the presence of severe hypertension.
• Urinalysis shows hematuria.
• Anemia suggests pre-existing renal disease.
• Microangiopathic hemolysis is common.
• Malignant arteriosclerosis small muscular
  arteries show segmental dilation and smooth
  muscle necrosis, loss of endothelial integrity,
  fibrinoid necrosis, rapid prolif of smooth muscle
  (onion skinning),
• Rx renal insuff
• Significant recovery may occur with blood
  pressure control and supporting dialysis.

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My impression

• Multiple complex interacting disease processes.
• Young male with a probable chronic anemia of
  malignancy, and renal failure. Renal failure
  itself may have a microangiopathic smear.
• Chronic hypertension as seen on renal biopsy.
• Metastatic adenocarcinoma may have associated
  chronic DIC with MAHA (Trousseaus syndrome)
• Marrow response low for the degree of anemia.
• Acute spikes of hypertension produce
  microvascular endothelial injury, especially of
  the kidneys, with platelet consumption and MAHA.
• Rx Start plasmapheresis and monitor since maybe
  HUS-TTP, but HUS is associated with malignancy,
  renal vascular hypertension and Gemzar, and not
  much success is reported.
• So support renal function with dialysis, control
  bp and malignancy all of which require aggressive
  treatment for good outcomes and which are
  potentially reversible forms of TMA, and chronic
  DIC.