22. Anticoagulation
LMW heparin, including dalteparin (Fragmin) and
enoxaparin (Lovenox)
 Standard of care for acute DVT (inpt or outpt) and
mild/moderate pulmonary embolism (inpatient only for
enoxaparin; off label but accepted use for dalteparin).
 Contraindications: significant renal failure, recent lumbar
puncture, spinal instrumentation, need for invasive
procedures, and extremes of weight (<50 or >100 kg)
 Dosing for DVT/PE treatment (full anticoagulation)
Pilot referral program
Anticoagulation Management Services
Outpatient care (Clinics One, Suite 144)
 Phone 617-726-2768
 Fax 617-726-2546
 Pager 30104
Transition Care, White 806B
 Phone 617-726-9616
 Fax 617-724-2976
 Pager 30103
 Dalteparin 100 IU/kg sc q12 hrs
 Enoxaparin 1 mg/kg sc q12 hrs
 Monitoring only indicated in modest renal failure, pregnancy, and wt <50 kg or >100 kg.
 Monitor with anti-Xa level drawn 4 hrs after 1st or 2nd dose; goal anti-Xa level is 0.5-0.85.
 T½ 4 hrs. Duration of anticoagulation 12-24 hrs.
 Pharmacologic reversal is difficult; protamine reverses only about 50% of the activity but can be
given for serious bleeding.
 Type II HIT is less common than with unfractionated heparin.
 Do not use in patients with known HIT.
Heparin, unfractionated
 Alternative to LMWH for treating DVT/PE (e.g. in
Dosing protocol for DVT/PE
settings of renal failure, extremes of weight, pending
Initial bolus 80 U/kg, initial infusion 18 U/kg
invasive procedure).
PTT
Action
 Goal PTT 60-85. Must be therapeutic within 24 hrs.
<
40
Bolus 5000 U, increase rate 300 U/hr
 Check PTT at 6 hrs after start and every rate change;
40-49
Bolus 2000 U, increase rate 200 U/hr
BID only when therapeutic.
50-59
Increase rate 100 U/hr
 T½ 90 minutes.
60-84
No change
 Coagulation normalized 6 hrs after discontinuation.
85-100
Decrease rate 100 U/hr
 Acute reversal, give protamine 20 mg/min iv, no more
101-150 Decrease rate 200 U/hr
than 50 mg over 10 min (about protamine 1 mg
>150
Hold 1 hr, decrease rate 200 U/hr
neutralizes heparin 100 U; need to take account half
life of heparin)
 Heparin-induced thrombocytopenia (HIT): avoid all heparin in type II, including flushes
 Type I: platelet drop first 48 hrs, but plts > 100K; HIT Ab negative; no thrombosis risk
 Type II: platelet drop at 5-10 days, <100K; HIT Ab positive; 30-50% risk thrombosis
Lepirudin (recombinant hirudin), a direct thrombin inhibitor






Presently indicated for HIT positive patients who require full anticoagulation for thrombosis.
Contraindicated in significant renal insufficiency (use argatroban below).
Acceptable in hepatic insufficiency.
Dosage: bolus 0.4 mg/kg IVP, continuous IV infusion 0.15 mg/kg/hr
Maximal dose regardless of weight: 44 mg IV bolus, 16.5 mg/hr IV infusion
Monitoring:
 Check PTT 4 hrs post initiation, with goal PTT 1.5-2.5X normal
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22. Anticoagulation
 If PTT < 1.5X, increase infusion 20%
 If PTT > 2.5X, decrease infusion 50%
 Recheck PTT 4 hrs after any change or at least once per day
 Renal failure requires significant dosage adjustment (consider argatroban instead):
 Bolus 0.2 mg/kg IVP, then
 CrCl 45-60: decrease infusion rate to 50% (0.075
mg/kg/hr)
 CrCl 30-44: decrease infusion rate to 30% (0.045
mg/kg/hr)
 CrCl 15-29: decrease infusion rate to 15% (0.0225
mg/kg/hr)
 CrCl <15: give bolus but no infusion
 Cannot be reversed. In event of bleeding,
discontinue infusion, supportive therapy.
Consider hematology consult for removal by
plasmapheresis.
 T½ initial 10 mins, terminal 1.3 hrs. Can be
prolonged to 2 days if CrCl < 15.
 Prior exposure can lead to antibody formation
which can markedly increase the t without
inactivating the molecule.
Anti-Xa level (also known as heparin assay)




When indicated, used to monitor patients receiving
LMWH, fondaparinux, or for patients on heparin who
also have lupus anticoagulant
Useful in renal failure, pregnancy, or obesity (data
limited for fondaparinux)
Anti-Xa level drawn 4 hours after LMWH or 3 hours
after fondaparinux
Therapeutic ranges for full anticoagulation
 Heparin 0.3-0.7 U/mL
 LMWH 0.5-0.85 U/mL
 Fondaparinux 0.5-1.2 U/mL (tentative)
Chromogenic X assay



Used for monitoring warfarin therapy in patients who
are receiving direct thrombin inhibitors (argatroban,
lepirudin)
Argatroban and thrombin raise INR levels and thus
INR not useful for monitoring response to warfarin
Chromogenic X levels 20-40% roughly equivalent to
INR 2.0-3.0
Argatroban, a direct thrombin inhibitor
 Direct thrombin inhibitor. Indicated in HIT positive patients who require full anticoagulation for
thrombosis.
 Contraindicated in significant liver dysfunction (use lepirudin above). Possible risk of allergic
reactions, increased when given jointly with contrast dye.
 Safe in significant renal insufficiency.
 Dosage: No bolus. Start 2 mcg/kg/min IV. Obtain baseline PTT off anticoagulation first.
 Monitoring
 Check PTT q2 hrs after start of infusion.
 Goal PTT 1.5-3.0X baseline, but <100.
 If PTT low, increase dose by 2 mcg/kg/min until PTT 1.5-3.0X baseline and < 100, or until maximum
dose 10 mcg/kg/min achieved.
 If used despite hepatic dysfunction, start at 0.5 mcg/kg/min iv.
 Cannot be reversed. If bleeding, d/c infusion, supportive therapy.
 T½ 40-50 minutes. Can be prolonged to >3 hrs if Child-Pugh score >6.
Warfarin
 Indicated for long-term oral anticoagulation.
 Starting dose 5 mg po qhs x 2-3 days, then per INR.
 Goal INR usually 2-3 for DVT/PE, TIA, or atrial fibrillation
 Higher for mechanical valves (see section on anticoagulation for prosthetic valves).
 Overlap with LMWH, heparin, or thrombin inhibitors required for 5 days, with 2 days after INR >2
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22. Anticoagulation
 INR will increase with decreased factor VII but antithrombosis does not occur until factor II is depleted
by warfarin, which requires approximately 5 days.
 T½ 40 hrs but highly variable depending on many drug interactions (e.g. digoxin, amiodarone).
 Reversal
 FFP, immediate but transient effect (lasts about 6 hrs).
 Vitamin K, 5 mg sc or po x 3 days; with normal liver function, reversal should begin within about 12 hrs.
 Recombinant activated factor VII, evolving use (see Ann Intern Med 2002;137:884)
Starting warfarin in patients on direct thrombin inhibitors
 Direct thrombin inhibitors affect the INR as well as the PTT, obscuring the effect of warfarin.
 Overlap for at least 5 days, as with heparin.
 Two monitoring alternatives:
 Chromogenic factor X level to assess the effect of warfarin (see box).
 Stop the thrombin inhibitor infusion for 3 hrs and check the INR and PTT. Then resume the infusion if
INR not therapeutic.
Coagulation cascade
IXa
IX
X
PC
APC
VIIa
Xa
II
VII
X
IIa
Jennifer Brown, M.D.
Andrew Yee, M.D.
MGH Medical Housestaff Manual
65
23. Oncologic emergencies
TUMOR LYSIS SYNDROME
Background
 Generally seen when effective chemotherapy is initiated against hematologic malignancies that are
rapidly growing or large volume, but can also occur spontaneously.
Etiologies
 Acute leukemias.
 Intermediate- or high-grade lymphomas: Burkitt’s, lymphoblastic, diffuse large cell.
 Risk is higher with bulky tumor masses, markedly elevated LDH or white count, or pre-existing
renal failure.
 Rarely seen with solid tumors.
Helpful studies and laboratory information
 The diagnostic laboratory test is a rising or elevated uric acid level plus:
 Hyperkalemia
 Hyperphosphatemia leading to hypocalcemia
 Oliguria leading to acute renal failure
Treatment
 The main goal is to prepare in advance to prevent complications—which are mostly due to
hyperkalemia and uric acid-induced nephropathy.
 Start allopurinol 300-600 mg po qd 24-48 hrs in advance of chemotherapy if possible.
 Start D5W with 3 amps (150 mEq total) of NaHCO3 at 200-250 cc/hr up to 24 hrs in advance.
 Goal urine pH >8.0. Follow urine pH q 8-12 hrs.
 Keep urine output at 200 cc/hr and fluid balance even; furosemide if necessary.
 Check uric acid, electrolytes, BUN/Cr, Ca, P, Mg at least every 6-8 hrs.
 Fulminant disease may require dialysis for control of hyperkalemia.
LACTIC ACIDOSIS
 Lactic acidosis can occur in patients with malignancy without evidence of poor tissue perfusion,
presumably due to anaerobic metabolism by the tumor cells.
 Rapidly progressive hematologic neoplasms, e.g. lymphoma, leukemia.
 Extensive hepatic metastases from solid tumors, e.g. small cell lung cancer.
 The only treatment is chemotherapy for the tumor and the prognosis is determined by the
responsiveness of the tumor.
SPINAL CORD COMPRESSION
Background
 Strongly consider in any patient with a solid tumor and back pain
 Most common presenting complaint in patients with cord compression, prior to onset of neurologic
deficits.
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23. Oncologic emergencies
 Early diagnosis is critical because neurologic status at the start of treatment is the best predictor of
neurologic status at the conclusion of treatment.
Etiologies
 Metastatic solid tumors, e.g. breast, lung, prostate, renal cell.
 Lymphoma or multiple myeloma.
Points to consider in evaluation





Back pain, often localized vertebral or radicular pain.
New onset of falls.
Lower extremity weakness or sensory disturbance.
Bowel or bladder dysfunction.
Check for






Lower extremity hyperreflexia,
Positive Babinski sign
LE weakness or sensory deficit,
Spinal sensory level
Decreased anal sphincter tone
Gait ataxia
Helpful studies and laboratory information
 Order urgent spinal MRI with cord compression protocol. This protocol performs limited images of
the entire spine, which is essential, as multiple sites of compression may be present.
 Thoracic sites are most common, followed by lumbosacral and then cervical.
Treatment
 Initiate dexamethasone 10 mg iv bolus, then 4 mg iv or po q6 hrs, immediately, if a patient with
known metastatic tumor develops back pain and neurologic deficits.
 Once the diagnosis is established by MRI, prepare for emergent radiation therapy or surgical
decompression (consult radiation oncology and/or neurosurgery and/or ortho spine).
Jennifer Brown, M.D.
MGH Medical Housestaff Manual
67
24. Fever and neutropenia
General considerations
 Guidelines adapted from ID guidelines (authored by Dr. Jay Fishman).
 Fever defined as single oral temp to >101F (38.3C) or persistent temperature >100.4F (38C)
 Neutropenia defined as absolute neutrophil count <500/mm3 or a count of <1,000/mm3 with a
predicted nadir of <500/mm3 within subsequent 48 hours.
 Consider infectious disease consultation in complex cases.
 Individualize treatment (prior infections, patient’s comorbidities e.g. renal dysfunction).
 No pathogen identified in up to 70% of cases.
 S. aureus and coagulase-negative Staph have become the predominant isolates. In past decade,
significant decline in P. aeruginosa infections; gram negative infections account for approximately
30% of isolates, E. coli and K. pneumoniae being the most common.
Points to consider in evaluation
 Duration and severity of neutropenia (see below).
 Neutropenic patients typically cannot develop significant inflammatory responses to infection, (e.g.,
an abscess may present with only mild tenderness).
 Check indwelling lines, mouth, at perineum, rectal area (rectal exam relatively contraindicated)
 Blood cultures with 2 sets including at least one peripheral culture; cultures from each indwelling
catheter; CXR, urine analysis and culture, if diarrhea, send stool for C. diff, bacteria, ova and
parasites
Therapy
 Generally cefepime 2 g iv q8h
 Discontinue previous prophylaxis if patient already on prophylaxis (e.g. with levofloxacin)
 In setting of suspected or proven intraabdominal or perineal infection, consider carbapenem
(e.g. meropenem) or cefepime/metronidazole
 In patients who are clinically unstable, consider addition of gentamicin (may need to individualize
based on renal function)
 Aminoglycoside may be helpful in documented gram negative bacteremia (e.g. hypotension)
 Penicillin allergy. Use levofloxacin (if not used for prophylaxis) and gentamicin or vancomycin
and aztreonam ± aminoglycoside (if levofloxacin used for prophylaxis)
 Vancomycin.
 Add for suspected catheter-related infection, known colonization with MRSA, known bacteremia with
gram positive organisms, possible known cardiac valve abnormality
 Add for possibility of severe mucositis (possible S. viridans bacteremia), 72 hour trial of vancomycin in
addition to cefepime; discontinue vancomycin if no clinical response, no identification gram positive
organisms nor clinical catheter infection documented
 Additional considerations
 Prolonged duration of neutropenia (>20 days), higher risk for gram negative bacteremia, consider adding
gentamicin
 Past history of frequent cephalosporin exposure (increased risk for resistant gram negatives), consider
adding gentamicin OR use of carbapenem
 Potential or witnessed aspiration (risk for anaerobic infection), consider adding clindamycin or use of
carbapenem
 Presence of colonizing organisms in stool or pharynx on surveillance cultures
MGH Medical Housestaff Manual
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24. Fever and neutropenia
 Non-albicans Candida species, consider adding an amphotericin product
 Mold (Aspergillus, Fusarium), consider adding a mold-active agent
 Pseudomonas, Enterobacter, Stenotrophomonas, consider adding gentamicin or agent to which organism is
susceptible
 Oral nonabsorbable antifungal therapy (e.g. nystatin, clotrimazole) should be added for all
patients receiving broad-spectrum antibacterial therapy
 G-CSF. Role of G-CSF in fever and neutropenia is controversial.
 G-CSF may shorten time of neutropenia; however may not necessarily reduce mortality.
 Resolution of fever
 Median time for resolution about 2-7 days (mean of ~5 days); in lower risk patients, duration shorter
(mean ~2 days)
 If patient defervesces, neutropenia resolves, and no organism is isolated, therapy may be stopped while
the patient is observed.
 If an organism is isolated or if there is an obvious source, once neutropenia resolves, antibiotics can be
changed to source-specific and given for an adequate course. However, if the patient is neutropenic,
broad-spectrum antibiotics should be continued even if a source is found, but adjusted accordingly.
Persistent febrile neutropenia
 If fever >72 hours despite antibiotic therapy without
Risk factors for invasive fungal infection
identifiable source, further workup indicated and
 History of invasive fungal infection prior
infectious disease consult should be strongly
to transplantation
considered.
 History of culture-negative febrile
 Consider untreated (or resistant) bacterial infection,
neutropenia during previous chemotherapy
 History of ongoing steroid therapy or
untreated viral infection, unrecognized invasive
steroid therapy prior to transplantation
fungal infection, graft v. host disease, or other factors

Underlying hematologic malignancy
(drug fever, toxic/therapeutic effects of
(particularly malignancy not in remission)
chemotherapy).
 Allogeneic transplantation (with unrelated
 Generally, probability of invasive fungal infection
or mismatched related recipients at highest
increases after 3-5 days, particularly in high risk
risk)

Duration of neutropenia >20 days
patients (such as allo BMT) and those with prolonged

Age >40
neutropenia (>20 days).

Prior history of CMV disease or CMV
 For those with risk factors for invasive fungal
viremia
infection, consider early initiation of antifungal
therapy.
 For those without risk factors, consider radiological workup with chest CT (to assess for early
invasive aspergillosis) and abdomen CT ( to assess for hepatosplenic candidiasis).
 Aggressive pursuit of CT abnormalities (e.g. BAL or biopsy) highly encouraged in order to establish a
microbiologic diagnosis.
Andrew Yee, M.D.
Jay Fishman, M.D.
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25. Chemotherapy regimens
Breast cancer
 AC – cyclophosphamide, Adriamycin
(doxorubicin)
 CA – cyclophosphamide, Adriamycin
 CAF – cyclophosphamide, Adriamycin, 5FU
 CMF – cyclophosphamide, methotrexate, 5FU
 CEF – cyclophosphamide, epirubicin, 5-FU
 TAC – Taxol (paclitaxel), Adriamycin,
cyclophosphamide
 Sequential AC/paclitaxel (Taxol)
 Paclitaxel/vinorelbine (Navelbine)
Colon cancer




5-FU + leucovorin
5-FU + leucovorin + irinotecan
5-FU + leucovorin + oxaliplatin
Capecitabine (Xeloda)
Prostate cancer
 Antiandrogen therapy
 Mitoxantrone + prednisone
 Estramustine (EMP) + docetaxel
Pancreatic cancer
 Gemcitabine
Hepatocellular carcinoma
 PIAF – cisplatin, interferon-alpha,
Adriamycin, 5-FU
Small cell lung cancer
 EP – etoposide, cisplatin
 CEV – cyclophosphamide, epirubicin,
vincristine
 CAV – cyclophosphamide, Adriamycin,
vincristine
 Irinotecan + cisplatin
Non-small cell lung cancer
 PE – cisplatin + etoposide
 PEI – cisplatin + etoposide + ifosfamide
 MVP – mitomycin, vindesine, cisplatin
MGH Medical Housestaff Manual
 GC – gemcitabine + cisplatin
 PC – paclitaxel + carboplatin
Germ cell tumors
 BEP – bleomycin, etoposide, cisplatin
 PVB – cisplatin, vinblastine, bleomycin
 VIP – etoposide, ifosfamide, cisplatin
AML
 “7+3” – 7 days of cytarabine + idarubicin on
the 1st 3 days as well for induction
 HiDAC – high dose cytarabine
 ADE – cytarabine, daunorubicin, etoposide
 ATRA – all trans retinoic acid (only for M3
type)
CML
 Interferon-alpha + cytarabine
 Imatinib (Gleevec)
CLL




Fludarabine
Cladribine
Rituximab
Alemtuzumab
Hodgkin’s disease
 ABVD – Adriamycin, bleomycin,
vinblastine, dacarbazine
 MOPP – mustargen, Oncovin (vincristine),
prednisone, procarbazine
 ESHAP – etoposide, Solu-Medrol,
cytarabine, prednisone
 ICE – ifosfamide, carboplatin, etoposide
 EIP – etoposide, ifosfamide, cisplatin
Non-Hodgkin’s lymphoma
 CHOP – cyclophosphamide,
hydroxydaunorubicin (Adriamycin),
Oncovin (vincristine), prednisone
 CHOP-R – above + rituximab
 MOPP – mustargen, Oncovin (vincristine),
prednisone, procarbazine
 ICE – ifosfamide, carboplatin, etoposide
70
25. Chemotherapy regimens
 EPOCH – etoposide, prednisone, Oncovin
(vincristine), cyclophosphamide,
hydroxydaunorubicin (Adriamycin)
 DHAP – dexamethasone, cytarabine,
cisplatin
Multiple myeloma




Dexamethasone alone
Thalidomide alone
MP – melphalan, prednisone
VAD – vincristine, Adriamycin,
dexamethasone
 TD – thalidomide, dexamethasone
 Bortezomib (Velcade, PS 341)
Hairy cell leukemia
 Cladribine
Targeted and new therapies
 Anastrozole (Arimidex) – direct inhibiter of
aromatase for breast cancer
 Trastuzumab (Herceptin) – anti-HER2/neu
protein monoclonal antibody for breast
cancer
 Rituximab (Rituxan) – anti-CD20
monoclonal antibody on B-cells
 Gemtuzumab ozogamicin (Mylotarg) – antiCD33 monoclonal antibody for AML
 Alemtuzumab (Campath-1H) – anti-CD52
monoclonal antibody for CLL
 Cetuximab (Erbitux) – monoclonal antibody
targeting epidermal growth factor
 Bevacizumab (Avastin) – monoclonal
antibody targeting VEGF
 Gefitinib (Iressa) – specific target of EGFR
TK domain for lung cancer
 Imatinab (Gleevec) – direct tyrosine kinase
inhibitor in CML and GIST
 Bortezomib (Velcade) – proteosome
inhibitor for treating multiple myeloma
 Capecitabine (Xeloda) – prodrug of 5-FU
for breast and colon cancer
Yi-Bin Chen, M.D.
MGH Medical Housestaff Manual
71
26. Bone marrow transplantation
General considerations
 Stem cell transplants are used to treat many conditions. Most common among them are the
leukemias, lymphomas, multiple myeloma, aplastic anemia, and myelodysplastic syndrome. Less
common indications include thallasemias, sickle cell disease, and autoimmune diseases.
 “Hematopoietic stem cell transplantation” (HSCT) is a broader term than the previously used “bone
marrow transplantation” (BMT), recognizing that there are multiple sources of stem cells for
transplantation.
Sources of stem cells
 Bone marrow. Harvested from the posterior iliac crests. The minimum number of CD34+ cells
from the marrow needed per transplant has not been well established, though approximately 10-15
cc of bone marrow per kilogram are harvested from the donor, which takes over 100 aspirates from
the bone marrow to achieve.
 Peripheral blood stem cells (PBSC). Stem cell (CD34+) production and release into the periphery
can be stimulated either by GM-CSF or G-CSF infusion, cytotoxic chemotherapy such as
cyclophosphamide, or a combination of the two. PBSCs are then harvested by leukopheresis from
the donor for transplantation. A minimum of 2 million CD34+ cells per kilogram to ensure reliable
engraftment. Benefits of PBSCT over BMT include more rapid hematologic reconstitution, and
improved quality of life. PBSCT are now the standard of care in autologous transplants. They are
being used in allogeneic transplants, though it may lead to a higher likelihood of chronic GVHD.
 Umbilical cord blood. Uncommonly used for HSCT at this time.
Types of transplants
 Autologous transplants. The recipient donates own stem cells prior to ablative therapy
 Allogeneic transplants. HLA-matched stem cells from a relative of the recipient, or an unrelated
donor. Cells are administered after their own bone marrow is ablated.
 Nonmyeloablative stem cell transplants. Also called “mixed chimeric” transplants or ‘minitransplants.” Allogeneic stem cells are infused after a non-myeloablative conditioning regimen,
leading to a marrow populated by both donor and host stem cells. The engrafted donor stem cells
may be effective alone, or donor leukocytes can be infused to induce a greater graft versus tumor
effect.
 Syngeneic transplants. Donor and recipient are identical twins. Higher failure rate due to decreased
graft-versus-tumor effect. GvHD is rare and is likely different than classical allogeneic GvHD.
Transplantation process
 Transplant day is day “0.” Patients are day –5 when they are 5 days prior to transplant, and day +60
two months post-transplant.
 Pre-transplant evaluation and donor screening
 Stem cells are harvested from donor (which may be the recipient in case of autologous SCT)
 Recipient marrow is ablated with a “conditioning” regimen (this may be total or partial depending on
type of transplant).
 Regimen consists of cytotoxic chemotherapy and/or total body irradiation (TBI). Usual conditioning
chemo regimens may include cyclophosphamide, busulfan, melphalan, or other alkylating agents.
 Stem cells engraft (locate to bone marrow and begin to produce cells).
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26. Bone marrow transplantation
 Engraftment is defined as the achievement of an ANC greater than 0.5. The process is also manifest
by increase in red cells and platelets, and may include fever, fluid retention and decreasing
potassium and phosphate levels.
 Autologous transplants engraft in approximately 10 days, while allogeneic transplants take 14-21
days. Delays in engraftment may be due to graft rejection, or viral infection (CMV, HHV, EBV)
 Monitor for and treat complications (more below)
 Management of immunosuppression continues throughout the transplantation process, minimizing
risk GvHD while maximizing the graft-versus-tumor Monitor for disease recurrence
Acute complications of HSCT (days 0 through +100)
 Engraftment syndrome (associated with allogeneic transplant more often than auto)
 During neutrophil recovery and engraftment, clinical syndrome of fever, erythrodermatous rash >25% of
body area, pulmonary edema as well as hepatic dysfunction, renal insufficiency, weight gain
 Occurs within 96 hours of engraftment
 Treated with corticosteroids, often with good response
 Graft versus host disease (GvHD). Acute GvHD is most common in allogeneic transplants, but can
complicate autologous and rarely syngeneic transplants. Presence of GvHD may correlate with a
beneficial graft versus tumor (GvT) effect. Involves skin, GI tract, and the liver.
 Skin. Usually the first system involved, and the most common. An erythematous maculopapular rash
generally involves the neck, ears, shoulders, trunk, the palms and soles. It can become confluent, and in
severe forms bullous and desquamating.
 Hepatic. Liver GvHD generally presents with elevated conjugated bilirubin and alk phos due to damage
to the bile canaliculi. The differential diagnosis of elevated LFTs after HSCT also includes venoocclusive disease of the liver (more below), drug toxicity and infection. May need liver biopsy.
 Intestinal. Manifests with diarrhea, and may lead to severe high output diarrhea with grave consequences.
Differential diagnosis of diarrhea post HSCT also includes C. difficile colitis and other infections, as well
as drug effects. Rectal biopsy may helpful for diagnosis.
 Treatment. Patients receive prophylaxis, generally with cyclosporine and methotrexate. Treatment of
acute GvHD begins with steroids as first line (usually methylprednisolone). Second line agents include
tacrolimus, antithymocyte globulin, and mycophenolate mofetil.
 Graft rejection. Most commonly seen with HLA mismatched transplants, T-cell depleted
transplants, and transplants for aplastic anemia. Manifest by failure to engraft, and has very high
mortality.
 Infection. Due to the high infectious risk secondary to the leukopenia that precedes engraftment,
HSCT patients are given aggressive antimicrobial prophylaxis. This generally includes a quinolone
for bacteria, TMP/SMX for PCP, acyclovir for HSV, fluconazole for Candida sp., and pre-emptive
ganciclovir if positive for CMV. Leukocyte production is stimulated with growth factors (G-CSF or
GM-CSF). Growth factor therapy is begun 24-72 hours post-transplant and continued until
neutrophil recovery is achieved.
 Veno-occlusive disease of the liver (VOD). Begins with injury to hepatic venous endothelium, and
is a procoagulant state. Risk factors include pre-existing liver disease, certain types of induction or
conditioning chemotherapy, high dose radiation, estrogen therapy, and mismatched transplants.
 VOD manifests as hyperbilirubinemia, jaundice, hepatomegaly, RUQ pain and weight gain secondary to
ascites. Patients receive ursodiol or low dose heparin for prophylaxis of VOD.
 Treatment is far more difficult, consisting of supportive care and may include tPA, LMWH, antithrombinIII, or defibrotide.
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26. Bone marrow transplantation
 Pulmonary disease. Pulmonary infections may occur with bacterial and fungal pathogens, and may
include viral pathogens such as CMV, RSV, influenza, parainfluenza, HSV, and adenovirus.
Mycobacterial and pneumocystis infections can occur. Other pulmonary complications include
diffuse alveolar hemorrhage, ARDS, and idiopathic pneumonia syndrome.
 Cardiac disease. Myocarditis or pericarditis may occur, generally related to conditioning
chemotherapy with high dose cyclophosphamide.
 Bleeding. Thrombocytopenia post transplant must be monitored carefully, and transfused generally
to keep over 20k. Single donor platelets should be used due to allo-immunization. HLA-matched
platelets are also an option for patients with high platelet-reactive antibodies. Bleeding sites may
include line sites, mucositis, bowel, and hemorrhagic cystitis, among others.
Chronic complications of HSCT (after day +100)
 Chronic GvHD. Presence of chronic GvHD is the most important factor determining long-term
outcome and quality of life following allogeneic HSCT. It occurs in 30 to 50% of allogeneic
transplants. It can occur after previous acute GvHD disease or without, though previous GvHD is
the strongest risk factor for the chronic form.
 Chronic GvHD leads to immunodeficiency by direct immunosuppressive effects of the GvHD, as well as
the immunosuppressive medications used for treatment, and therefore a legion of infections can occur.
Manifestations are similar to chronic autoimmune diseases such as SLE, scleroderma, and primary biliary
cirrhosis. Primary involved organs in chronic GvHD include skin, GI tract, liver, and lungs.
 Skin. May be diffuse or limited. Diffuse disease involves generalized erythema and desquamation, and
may involve to resemble scleroderma or lichen planus.
 GI tract. Marked by dry mucous membranes and painful ulcerations. Esophageal involvement may lead
to ulcerations, strictures, and webs. Small and large bowel involvement may lead to chronic diarrhea and
malabsorption syndromes.
 Hepatic. May lead to chronic hepatitis and cirrhosis
 Lung. Bronchiolitis obliterans can occur and presents with dyspnea and dry cough. Pulmonary fibrosis
secondary to chemotherapy or radiation also must be considered.
 Treatment. Consists primarily of immunosuppression with typical agents such as steroids, cyclosporine,
azathioprine, and tacrolimus. Newer agents include thalidomide, mycophenolate mofetil, rituximab, and
rapamycin.
 Infection
 Infections due to the immunocompromised state can include bacterial, fungal, viral (especially CMV and
RSV), PCP, and mycobacterial pathogens.
 Posttransplant lymphoproliferative disease (PTLD)
 EBV-related and seen primarily in recipients of T-cell depleted allografts. May consist of a polyclonal Bcell proliferation presenting as an infectious mononucleosis-type illness, with or without evidence of early
malignant transformation. A second form is a malignant, monoclonal, and primarily extranodal B-cell
proliferation.
 Treatment for the benign form consists of reducing immunosuppression, and advanced therapy only if
that fails. The malignant form is treated with rituximab with or without chemotherapy and radiation.
Prophylactic rituximab is being investigated in patients with EBV reactivation.
 Secondary malignancy.
 Hematologic malignancies, such as AML and MDS, as well as non-hematologic malignancies, are
increased in the post HSCT population. The patterns of post transplant malignancy differ by indication
for transplant, type of conditioning regimen used, and other factors.
Jeremy Abramson, M.D.
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27. Transfusion guidelines
Red blood cells
 1 unit = 300 mL: 200ml RBC, 100 mL plasma (Hct
= 70%); it increases patient’s Hct 3-4% per unit
Indications
 Symptoms of anemia (levels vary), acute blood loss
 Hct < 21. Maintain Hct 21-24 in critical illness
(except in acute coronary syndromes)
 Hct < 25 significant underlying cardiovascular
disease
 To “prevent ischemia”
Infectious risks
Hep A
1/1x106 U
Hep B
7-32/1x106 U or 1 in 63,000
Hep C
4-36/1x106 U or 1 in 103,000
HIV
0.4-5/1x106 U or 1 in 493,000
HTLV
0.5-4/1x106 U or <1 in 100,000
Parvo B19
100/1x106 U
CMV
“common”
 Age < 40, Hct <24
 Age 41-60, Hct <27
 Age 61-70, Hct <30
 “Massive blood transfusion” = transfusion >50% of patient’s blood volume in 12-24 hrs
Complications
 Dilution of coagulation factors and platelets
 Check PT, PTT, Plt after every 5-7 U PRBC transfused
 Transfuse 2 units FFP when PT, PTT are 2x control
 Transfuse 6-pack platelets when platelets <50,000
 Metabolic alkalosis: secondary to sodium citrate + citric acid used to anticoagulate blood
 Electrolyte disturbances: decreased calcium (chelated by citrate) & increased potassium (from PRBC
hemolysis)
 Hypothermia
Platelets
 6 unit pooled platelets (or 1 unit single donor) increases platelet count by 30,000
Indications
 <10,000
 <20,000 with bleeding, coagulation disorder, infection, or bedside procedure
 <50,000 with major bleeding or pre-procedure
 Fatal hemorrhagic complications do not occur without first developing extensive mucous membrane
bleeding.
Contraindications
 TTP/HUS
 HIT (heparin induced thrombocytopenia)
Forms
 Pooled platelet concentrates: regular form
 Single-donor: lower risk of contamination, donor exposure, leukocyte contamination and adverse
reactions
 Leukocyte-reduced: decreases leukocyte reactions, alloimmunization and platelet refractoriness
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27. Transfusion guidelines
Complications
 Platelet refractoriness: platelet increase less than 5000. Consider: sepsis, DIC, BMT, splenomegaly;
alloimmunization
 Platelet alloimmunization
 Diagnosis: abnormal platelet recovery 10 min-1 hr post-transfusion
 Check PRA (panel reactive antibody), determine HLA type, can try ABO identical donor, fresh
platelets, but will not be effective if have alloimmunization
 If PRA positive, transfuse with HLA-matched platelets
 If PRA negative, cross match single donor platelets with patient’s serum
 If acutely bleeding consider aminocaproic acid (if no risk for DIC)
 Consider: corticosteroids, IVIG, splenectomy
 Prevention: use leukocyte-reduced or irradiated platelets
Fresh frozen plasma (FFP)
 Contains all the requisite plasma coagulation factors
 Never used as a source for specific clotting factors
 Lasts approximately 4 hours so must transfuse frequently
Indications
 Bleeding due to deficiency of coagulation factors and PT >17 secs
 Elevated PT prior to procedure
 Prophylaxis for PT >30, INR >8
Cryoprecipitate
 Contains vWF, factor VIII, fibrinogen, factor XII, usual dose = 8-10 units
Indications
 VWD
 Hemophilia
 Fibrinogen <100 mg/dL with bleeding
 Pre-procedure
 Dilution
Specialized Components
Leukocyte reduced (LR). Available for pRBC, platelets
 Decreases febrile nonhemolytic transfusion reactions, decreases HLA-sensitization, decreases CMV
transmission
 Indications:







Chronically transfused patients
Potential transplant recipients
Patients with previous febrile nonhemolytic transfusion reactions
Immunocompromised
Pregnant women
Chemotherapy
CMV-seronegative at-risk patients for whom seronegative components are not available
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27. Transfusion guidelines
Irradiated cells. Available for pRBC, platelets, FFP
 Prevents GVHD, does not remove lymphocytes from blood
 Indications:
 Hereditary immunodeficiency states
 PRBCs from relatives in donation programs
 Immunosupressed by chemotherapy
Washed cells. Available for pRBC, platelets
 Eliminates complications with infusion proteins (prevents complement infusion).
 Indications:




Recurrent/severe allergic reactions
IgA deficiency and no IgA-deficient donors available
T-activated red cells
Complement-dependent autoimmune hemolytic anemia
Frozen deglycerolized red cells
 Indication: IgA deficiency for whom IgA donors do not exist
Adverse reactions
 Affects 1-6% of all blood transfusions (includes immunologic, infectious, chemical, and physical
adverse reactions).
 Note that there is a special form and lab requisition slip that can be filled out if an adverse reaction is
suspected.
Type
Of note
Symptoms
Cause
Rx
Febrile NonHemolytic
Transfusion
Reaction
 Most common
 Benign, but similar to
AHTR
 15% will have a 2nd
reaction
Fever, chills, +/- mild
dyspnea within 1-6
hrs after transfusion
Class I HLA Ab vs.
contaminating
leukocytes. Mediated
by cytokines
Acute
Hemolytic
Transfusion
Reaction
 Fever and chills may be the
only manifestation
 Plasma may be pink
 Results in DIC, shock,
acute renal failure
Fever, flank pain,
red or brown urine.
Destruction of donor
RBC by preformed
recipient Abs. Usually
secondary to ABO
incompatibility
Delayed
Hemolytic
Transfusion
Reaction
 Can be secondary to:
transfusion, transplantation,
pregnancy.
 2-10 d post transfusion
 Gradual, less severe.
Slow Hct drop, slight
fever, increase in
unconjugated
bilirubin, spherocytes
Amnestic Ab response
from re-exposure to
foreign red cell Ag
 Stop the transfusion and rule out
hemolytic reaction
 Give antipyretics, meperidine in pts with
chills and rigors
 Use leukoreduced blood products in the
future
 Stop the transfusion, leave IV attached
for treatment
 Start NS at 100-200 cc/hr to support
urine output >100 cc/hr.
 From other arm obtain sample for direct
antiglobulin test (will be positive);
plasma free hemoglobin; save a urine
sample for Hb testing.
 No heparin for 12-24 hrs to prevent
DIC.
 May require pressors; watch for
hypokalemia.
 None in absence of brisk hemolysis.
 Inform patient of future transfusion risk
as same antigenic red cell could be
harmful.
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27. Transfusion guidelines
Anaphylactic
transfusion
reaction
 Rapid onset
 Primarily in East Asians
 Prevent by using IgAdeficient blood or ultrawashed products
Rapid anaphylaxis
including shock,
hypotension
angioedema,
respiratory distress
Due to presence of
specific IgG and anti
IgA Abs in pts IgA
deficient
 Immediately stop transfusion
 Methylprednisolone
 Epinephrine 0.3 mL of 1:1000 solution
IM
 Manage airway and O2
 Vasopressors if necessary
Transfusion
Related
Acute Lung
Injury
 Occurs in 1:2000
 Occurs 2-4 hrs after onset
of transfusion
 CVP is normal
 Cannot distinguish from
ARDS
 Death <10%
Acute resp. distress,
hypoxemia,
hypotension.
Fever, pulmonary
edema without LV
failure
Due to pulm. leukoagglutination reaction
resulting from donor
Abs against recipient
granulocytes
Post
Transfusion
Purpura
 Uncommon
 Occurs mostly in women
 Occurs 5-10 days after
transfusion of plateletcontaining products
Severe
thrombocytopenia
lasting days to weeks
ITP due to
sensitization to a
foreign antigen by
pregnancy or
transfusion
Transfusion
Associated
Graft versus
Host Disease
(GVHD)
 Rare and almost always
fatal
 Occurs in pts with immunodeficiency
 Develops 4d-1mo after
transfusion
 Not induced by FFP, cryo
or frozen deglycer. red cells
 Dx suggested by skin
biopsy & lymphocytes with
different HLA phenotype
from host cells
Dysfunction of skin,
liver, GI tract, bone
marrow. Fever,
anorexia, abd pain,
vomiting, diarrhea,
cough, erythematous
maculopapular rash
Lab: pancytopenia,
abnl LFTs
Attack by viable donor
lymphocytes on
recipient’s lymphoid
tissues
 Stop transfusion
 Notify blood bank and draw large purple
top
 Supportive therapy
 Consider diuretics
 High dose steroids have been used,
appear ineffective
 No more plasma containing blood
products from implicated donor
 If recovers, not at increased risk for
recurrent episodes following
transfusions from other donors
 Preferred therapy is IVIG in high doses
(400-500 mg/kg per day x 5 d)
 If severe, IVIG 1.0 g/kg per day x 2 d
 Takes 4 d for platelet count to exceed
100,000
 Only washed cells or HPA-la negative
in future
 No therapy
 Prevent by using irradiated products
Kelly Richardson, M.D.
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