hematologic and oncologic emergencies wes miller fellow, pediatric hematology and oncology october 31 2007

objectives: AMBITIOUS!
• review common presentation, pathophysiogy and (emergent) management of the following
– the bleeding hemophiliac
– “the bleeding patient with immune thrombocytopenia purpura (ITP)”
– tumor lysis syndrome in the patient with a new malignancy
– hyperleukocytosis in acute leukemias or myeloproliferative disease (MPD)
– typhlitis
– superior vena cava syndrome in the patient with a mediastinal mass

the sickler...
• presents a whole new set of emergencies
– potential for great morbidity and mortality
• more familiar to most ED docs in Atlanta
• not addressed here

but, first...
for the job you do for out patients
• we realize our patients are
• our attitude on the phone is often one of
– at risk population
– subtleties matter

the bleeding hemophiliac
• 8 month old male
• presented to PMD with 1 week hx of progressive bilateral LE weakness
– diagnosed with GBS, sent to SR ED
• at SR ED, noted to have multiple bruises over body ( not just over shins ), many nodular and hard
• history of sublingual frenular bleed x 10 days following mild trauma in past
• history of 2 weeks of oozing at surgical site following neonatal circumcision
• history of LP at 6 weeks of life for fever (RSV)
– waxing and waning “bulging bruise” at site EVER
SINCE

the bleeding hemophiliac
• family history negative for bleeding disorders
• child with history of vit K ppx at birth, no warfarin or rat poison exposures, no recent antibiotics or diarrhea.
• Formula fed; typical baby foods
• PE: alert, smiling, clapping. VS wnl. no spontaneous movement of BLE, no withdrawal from painful stimuli, patellar areflexia
• CBC normal, platelets robust
• PT: 12.6 seconds (normal)
• PTT: 125.6 seconds (not normal)
• ultrasound: massive thoracolumbosacral paraspinal hematoma

the bleeding hemophiliac

the bleeding hemophiliac
• normally, the known hemophiliac will present to your ED
• hemophilia
– A (“classic”): factor 8 deficiency
– B (“christmas disease”): factor 9 deficiency
– both coded on X chromosome
– disease due to absent or dysfunctional protein
– clinically INDISTINGUISHABLE
– prevalence: 1 in 7500 males
– hemophilia A seven times more common than hemophilia B

the bleeding hemophiliac
• hemophilia graded according to degree of factor dysfunctionality:
– severe: <1% native activity
– moderate: 1% - 5% native activity
– mild: >5% native activity
• where do hemophiliacs bleed?
– everywhere!!!
– mucocutaneous bleeds (epistaxes, oral, GI)
– SOFT TISSUE BLEEDS
• HEMARTHROSES!!!!!
• muscle bleeds (ileopsoas!)
• eyes, renal/GU, throat
• CNS !!!!!!!

the bleeding hemophiliac
• treatment options
– respective recombinant factor replacement
(both F8 and F9 deficiency)
– DDAVP (mild factor 8 deficiency)
– FFP **** (factor 9 deficiency)
– cryoprecipitate **** (factor 8 deficiency)
– antifibrinolytics (amicar)
• treatment strategies
– “on demand”
– primary prophylaxis
– secondary prophylaxis

the bleeding hemophiliac
– recombinant factor 8 dosing:
• 1 unit/kg of factor 8 raises the activity level 2%
– recombinant factor 9 dosing:
• 1.5 unit/kg of r-factor 9 raises the acvity level 1%
• beware anaphylaxis in F9 replacement
– when in doubt, treat!!!!
– correct the bleeding hemophiliac child to 80%
- 100% activity

the bleeding hemophiliac
– 25% - 30% in F8 deficiency
– 3% in F9 deficiency
– FEIBA
• do not use antifibrinolytics with FEIBA
– recombinant VIIa (novoseven)
– antifibrinolytics (amicar)

ITP
• 3 y/o male presents with sudden onset , 1 day history full body petechiae and purpura
• no epistaxis, melena, hematochezia, hematuria, no h/a, no emesis
• no recent fever, no bony pains; excellent energy and appetite
• no chronic medications, but mom gave robitussin 2 weeks ago for “cold”
• mom frantic: just saw FoxNews special and wants to know if child dying of “meningitis”

ITP
• PE: vs wnl
• child jumping up and down on exam bed
• 8 year old brother then tackles patient who is giggling and about to fall off the bed
• head to toe petechia and purpura
• OC with multiple purpura, none oozing
• CN exam normal, neuro exam normal
• no HSM
• CBC with differential:
– WBC 6k/microL, relative lymphocytosis, 10% atypical lymphocytes, ANC 2000
– hgb 11.8 g/dL
– platelets <10k/microL

ITP
• the most common AI disorder affecting a hematologic element (1:10,000 kids/year)
• peak age: 2 - 6 years
• males = females (children)
• 2 flavors:
– acute (spontaneous resolution < 6 months)
– chronic (persistance > 6 months)

ITP
• cause: macrophagic destruction of antibody-sensitized platelets
– occurs in RES
– primary site: spleen
• clinical course
– usually, antecedent viral illness/vaccination in weeks prior to onset
– abrupt onset bleeding/bruising
– otherwise HEALTHY kid

ITP
• how low do they go??
– plts < 20K: over 80%
– usually isolated : expect normal WBC, hgb
• anemia in 15% of cases: extracorporeal losses
• splenomegaly?
– palpable spleen present in 10%
• peripheral smear “mandatory”
– confirm true t’penia (rule out spurious!)
– may see large plts
– important negatives:
• no WBC abnormalities
• no evidence of MAHA
• no evidence of AIHA
• other work-up:
– direct antibody test (DAT/direct Coomb’s)
– ABO/Rh blood type

treatment
ITP

ITP
• where, exactly, do ITP kiddos bleed??
– “most” with petechiae/ecchymoses/purpura
– epistaxis/oral wet purpura in < 30%
– GI (melena/hematochezia), hematuria in < 10%
– menorrhagia in appropriate age group
ICH: 0.1% - 0.9%
• how prone to serious bleeding are ITP patients??
– not very!!!
– concept of total body platelet mass
– bone marrow: LOTS of megakaryocytes!
– compare to other thrombocytopenic contexts
• iatrogenic post chemo!
– risk stratification with absolute platelet count
• < 20K/microL: greatest
• 20K - 50K/microL: moderate
• >50K : insignificant

ITP
– suspected ICH
– known ITP with significant trauma
– recurrent or unabating mucosal bleeding
– anemia secondary to loss
– rarely: extenuating social situation
NOT
– parental anxiety
– petechiae or purpura, no matter how florid

ITP
• management armamentarium
1. educate, educate, educate
2. anticipatory guidance
3. counsel to avoid antiplatelet meds (ASA, NSAIDs)
4. Platelets are NOT TYPICALLY HELPFUL****
5. observation is commonest strategy
6. WinRho : monoclonal anti-Rho D antigen antibody
1.
only for non-anemic, DAT negative, Rh+ patients
7. IVIG
8. steroids*****
9. other immunomodulatory agents
10. splenectomy

ITP
• to marrow or not to marrow ???
– good concensus: do not marrow if
• clinical gestalt consistent with ITP
• plan observation alone
• plan IVIG and/or anti-D therapy
– debatable
• plan corticosteroid treatment (even in kids with clinical constellation classic for ITP)
– good concensus: marrow if atypical clinical picture
• natural history:
– resolution in 50% by 4 - 8 weeks
– resolution in 65% by 3 months
– resolution in 75% by 6 months
– 1/3 of “chronic” patients will spontaneously resolve
– factors associated with chronicity:
• females
• age older than 10 (also very young?)
• insidious onset

tumor lysis syndrome (TLS)
• 8 year old male presents with rapidly distending abdomen , first noticed 4 days ago
• febrile, anorexic, pale; stooled yesterday; decreasing UOP
• PE: mild distress, large palpable discreet mass in right lower abdomen
• CT: large mass near ileocecum
• CBC:
– WBC 10 K/microL
– 3% blasts
– mild anemia.
• chemistries:
– LDH 22,000 U/L (quite high)
– uric acid: 12 mg/dL (quite high)
– K: 6.1 mmol/L (elevated)
– creatinine: 1.3 mg/dL (elevated)
– phos: 9 mg/dL (elevated)

TLS

TLS
• sudden burden of intravascaular potassium, phosphate and uric acid spilled by dying tumor cells
– rhabdomyolysis
– crush injuries
– thermal injuries (burns/hypothermic exposure)
• secondary to massive synchronous release of intracellular contents into extracellular space
• typically seen at initiation of therapy for new malignancy, but MAY BE SEEN AT PRESENTATION
• consequences:
– acute renal failure (urate and CaPhos crystal tubulopathy)
– cardiac dysrhythmias
– acute hypocalcemia

TLS
• identifying patients at risk:
– lymphomas :
• classically, Burkitt’s lymphoma (practically, any NHL with short doubling time and bulky disease)
– leukemias :
• especially with high peripheral WBC (>100k/microL)
• especially with large extramedullary disease burden : massive HSM, bulky T cell leukemia/lymphoblastic lymphoma
• especially with nephromegaly : suggests leukemic renal parenchymal involvement
– lymphoproliferative disorders
• CML, JMML

TLS
• interventions:
– hyper-hydration :
• beware of oliguria
• 2-3 x maintenance of NON POTASSIUM CONTAINING IVF
• ?alkalanization
– NOT AT CHOA
– kayexelate (ideally, oral only), concomitant insulin and glucose, albuterol, CaGluconate****
– renagel
– be CAUTIOUS: give supplemental calcium only with
EKG changes with hyperkalemia or symptomatic hypocalcemia
• goal: keep calcium-phosphate product LOW (<60)

TLS
• interventions:
– allopurinol
• inhibits hypoxanthine oxidase
• enzyme critical in metabolic pathway from purine → →
→uric acid
– rasburicase
• urate oxidase
• converts uric acid to soluble metabolite (allantoin)
• $$$$$
• consult with heme/onc before giving
– begin treating malignancy !!!!

hyperleukocytosis
• 7 year old male presents to SR ED with CC of decreased energy x 7 days, unresponsive today
• exam:
– combative, confused, averbal
– pupils anisocoric, but responsive
– hemiparesis
– pallor
– tachycardic with gallop
– massive HSM
• CBC:
– WBC: 327K/microL, 94% blasts
– hgb: 4.6 g/dL
– plts: 16K/microL
• DIC panel:
– PT: 24 seconds (prolonged)
– PTT: 28 seconds (normal)
– firbrinogen: 60 (low)
– DDimers: 4100 (elevated)

hyperleukocytosis

hyperleukocytosis
• patient intubated
• surgery emergently consulted to place vas-cath
• patient leukapheresed x multiple cycles in PICU
• flow cytometry: acute T-cell lymphoblastic leukemia
• progressed to renal failure, CVVH
• worsening neurologic picture, unilateral fixed pupil
• neurosurgery: cranial flap

hyperleukocytosis

hyperleukocytosis
• presence of excessive blastemia in the leukemic
• defined by peripheral WBC of at least
100K/microL
• risk of symptomatology greatly increased for counts of 300K/microL or more
• risk of symptomatology greatly increased in AML and CML with increased circulating myeloblasts
• seen in
– AML: 5%- 20% at presentation
– ALL: 9% - 13% at presentation
– CML: nearly all patients at presentation

hyperleukocytosis
• pathophysiology:
– supraphysiologic whole blood viscosity :
LEUKOSTASIS
– aggregation of blasts in microvasculature
• rheologic properties of MYELOBLASTS contribute to worse outcomes in AML or CML
– larger than lymphoblasts
– less distensible than lymphoblasts
– “stickier” than lymphoblasts

hyperleukocytosis
• Pathophysiology
– inappropriate activation of soluble phase clotting cascade
– microvascular occlusion
• distal ischemic injury/metabolic acidosis
• MAHA (on top of myelophthistic cytopenias)
• DIC
• reperfusion hemorrhage
– MSOF (CNS, pulmonary, renal, hepatic, cardiac, dactylitis, priapism, etc.
)

hyperleukocytosis
• Interventions   DECREASE WHOLE
BLOOD VISCOSITY :
– primary intervention: CYTOREDUCTION
• leukapheresis
• cytoreductive chemotherapy
– immediately notify heme/onc
• we will urgently activate ARC cytapheresis folks
– in the meantime, tip balance to LESS viscosity
• immediately begin hyper-hydration (2-3 x maintenance) with non-K+ containing IVF
• AVOID PRBC transfusions !
– markedly increase whole blood viscosity
– if necessary, transfuse with ceiling hgb of 8-9 g/dL
• may transfuse platelets liberally if necessary

hyperleukocytosis
• interventions:
– correct coagulopathy ???
• depends!
– make plans for urgent placement of vas-cath
– manage TLS
• who gets leukapheresed ?
– ANY PATIENT WHO IS SYMPTOMATIC FROM
SUSPECTED LEUKOSTASIS SYNDROME
– asymptomatic patients:
• suspected AML : WBC > 100K/microL
• suspected ALL: WBC > 200K/microL
• suspected CML: WBC > 200K/microL

typhlitis
• 4 year old female
• fever to 103, abdominal pain, emesis, bloody diarrhea x one day
• undergoing induction chemotherapy for standard risk, Bprecursor ALL
– finished 2 week steroid course 3 days go
• exam:
– toxic appearing
– tachycardic and hypotensive
– mild abdominal distension, hypoactive bowel sounds
– guarding on abdominal exam with marked TTP in RLQ
– Central capillary refill > 5 seconds
• KUB and cross-table lateral: no free air, possible pneumatosis intestinalis noted
• CT abdomen: marked cecal bowel wall thickening , peumoatosis intestinalis present

typhlitis
• inflammation of the bowel wall, especially at the level of the cecum
• seen in children with PROLONGED and
PROFOUND neutropenia
• Increased risk following chemotherapeutic drugs which cause mucositis
• pathogenesis is essentially parallel to neonatal
NEC (nectrotizing enterocolitis)
– transmural bacterial translocation: PI
– risk of bowel perforation
– risk of translocated bacteremia: SIRS
• pseudomonas aeruginosa
• clostridium septicum

typhlitis
• at risk patients:
– leukemics or NHL patients in induction
• may be seen in consolidation for higher intensity regimens
– following systemic cytarabine (ARA-C) therapy
• especially post high dose cytarabine
– any patient with prolonged, profound neutropenia
– beware the child “in leukemic induction, coming off steroids, with sudden fever and acute abdomen/signficant RLQ pain”

typhlitis
• interventions:
– fluid resuscitation
– blood culture; stool culture if available
– avoid rectal exam
– empiric broad spectrum antibiotics (GP, GN, anaerobic coverage)
• vancomycin, meropenem +/- aminoglycoside
– evaluate for perforation (KUB/CT)
• surgery consult if present
– inotropic support for hypotension unresponsive to fluid resuscitation

superior vena cava syndrome
• 12 year old male, previously healthy
• 6 week history of worsening cough
– treated 1 week into symptoms with 2 weeks of systemic steroids for “bronchitis”
– initially cough improved and felt much better
– now worsening
– 20 pound weight loss
• past week:
– worsening orthopnea (sleeping upright in chair)
– fevers
• past 2 days:
– expanding mass in supraclavicular area

SVCS
• exam:
– alert and non-toxic; completely oriented
– facial edema
– no stridor, not dyspneic
– tachypneic, absent breath sounds R lung
– palpable, firm nodes in right supraclavicular chain
– splenomegaly

SVCS

SVCS

SVCS
• CBC:
– WBC: 12K/microL, 13% blasts
– hgb: 11.9 g/dL
– plts: 144K/microL
• quantitative βhCG (tumor marker): normal
• quantitative AFP (tumor marker): normal
• stat peripheral flow: T cell acute lymphoblastic lymphoma (leukemia?)

SVCS
• Interventions:
– ICU observation
– begun on empiric high dose solumedrol
• based upon presence of blasts in smear
– next day, begun on induction chemotherapy per flow cytometric diagnosis

SVCS
• signs and symptoms from impedence to flow in the SVC
– plethora
– facial edema
– JVD
– dyspnea
– orthopnea
– cough
– stridor
• for advanced SVC obstruction, may see
– confusion
– lethargy
– headache
– vision changes
• usually, abnormal SVC flow results from extravascular compression, not a primary intraluminal thrombus

SVCS
• causes: mediastinal badness
– malignancy
• NHL (70% of malignant causes of SVCS)
• HL
• neuroblastoma
• leukemias***
• germ cell tumors
– granulomatous disease
– aortic aneurysms
– primary SVC thrombus

SVCS
• accurate diagnosis is critical...
• ...however, tissue acquisition can be problematic
– do NOT sedate
– do NOT give anxiolytics
– avoid anything which will compromise
• muscular tone
• venous return
• an already taxed cardiopulmonary state

SVCS
• workup:
– CXR, CT to evaluate mass location, size, airway patency, encasement of vessels, presence of pleural effusion , etc.
– evidence of hematolymphoid malignancy?
• BLASTS on peripheral smear
• empirically send peripheral blood flow cytometry
• bone marrow aspirate and biopsy under local anesthesia
– meticulous lymphatic exam
• may reveal tissue source obtainable via local anesthetic only
– urine catecholamines (VMA/HVA) if clinical picture consistent with neuroblastoma
– serum QUANTITATIVE (tumor marker) βhCG and AFP for GCT
– transthoracic echocardiogram: presence of pericardial effusion
– PPD/ID titers

SVCS
• consult anaesthesia for symptomatic or unstable patient
• unstable for general anesthesia:
– >50% reduction in cross-sectional diameter of trachea at any level
– <50% predicted PEFR on PFT’s

SVCS
• interventions:
– ultimately, begin treatment for underlying cause
• however, may BE FACED WITH UNSTABLE
PATIENT and no diagnosis:
– awaiting pathologic analysis of obtained sample, or
– danger of obtaining any sample for tissue diagnosis
• initiate empiric therapy:
– solumedrol: 2 mg/kg/day divided tid
– external beam radiation
– if high clinical suspicion of GCT or NBL, initiate appropriate chemotherapy