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Hem/Onc Emergencies

Critical Care Interest Group

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Outline

  • Thrombotic Microangiopathies
    • DIC
    • TTP
    • HUS
    • CAPS
  • HLH
  • TLS
  • APL
  • Blast Crisis

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Thrombotic Microangiopathy Groups

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I: TTP

II: Atypical HUS

III: HUS

IV: DIC, HELLP Syndrome, catastrophic antiphospholipid syndrome, HIT

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Disseminated Intravascular Coagulation (DIC)

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DIC

  • Epidemiology
    • 9-19% of ICU patients have DIC
    • Mortality rate of 45-78%

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  • Pathophys: Wide-spread consumptive coagulopathy leading to clotting throughout microvascular structures and possible end organ damage

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  • Clinical Presentation: It is a secondary process and so patients will present with signs and symptoms of the initiating primary pathology
    • Thrombosis predominant commonly presents with end organ damage
    • Bleeding predominant will present with active bleeding

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DIC Diagnosis

  • ISTH Scoring system
  • Labs
    • Low fibrinogen
    • Thrombocytopenia
    • Prolonged PT
    • Increased d-dimer
    • Increased LDH
    • Anemia

ISTH Criteria for DIC

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DIC Treatment

Treat the underlying insult!!!

    • Platelets transfused goal > 50 × 109/L
    • Fibrinogen replaced via cryo or FFP to goal of 150 mg/dL (1.5 g/L)
    • FFP transfused to goal of PT and PTT within 1.5x normal values
    • RBCs transfused to goal of 7-8 g/dL

Bleeding Predominant

    • ISTH recommends therapeutic LMWH however evidence is sparse
    • Some reserve AC for macrothrombus (ie. PE)

Thrombosis Predominant

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Thrombotic Thrombocytopenic Purpura (TTP)

Epidemiology

    • 2-4 million patients a year
    • Women account for 79%, African Americans and obese are at higher risk
    • Mortality has declined from 90 to 10%!

Pathophysiology: Deficiency in ADAMTS13 (metalloproteinase) 🡪 von Willebrand factor multimers accumulate 🡪 microvascular thrombosis & microangiopathic hemolytic anemia

    • Hereditary TTP manifests in childhood
    • Acquired TTP
      • 50% idiopathic
      • The reminder are secondary to infection, pregnancy, autoimmune, HIV, pregnancy, cancer, organ transplant

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TTP Diagnosis

Clinical Presentation

    • “Classic Pentad” (4% of patients): fever, microangiopathic hemolytic anemia, thrombocytopenia, renal dysfunction, neuro deficits
    • Most common is neuro deficits 50%, renal failure 5% , fever 10%
    • Majority do have platelet count < 20 × 109/L and <30% hematocrit

Labs to Consider

    • CBC w/ diff, smear, LDH, haptoglobin/INR, PTT, Type & Cross
    • BMP, LFTs, troponin, lactate
    • Cultures, HIV screening, ADAMTS13 levels (sensitivity & specificity not great)

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Diagnosis and Decision Making

  • PLASMIC (Platelets, Lysis, Active Cancer, Stem cell or solid organ transplant, MCV, INR, and creatinine) score
    • Score 6-7 has sensitivity of 90% for TTP and reliably predicts response to plasma exchange
    • Score 0-5 has 90% sensitivity for predicting absence of TTP and low response to plasma exchange
      • Score of 0-4 is 100% for predicting absence

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PLASMIC Score

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Spotlight Corner: Plasma Exchange

  • Replaces patients' plasma with donor plasma

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  • Requirements: Apheresis or hemodialysis catheter placement

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TTP Treatment

  • Replenish ADAMTS13 and remove/reduce offending antibodies
    • Accomplished with plasma exchange

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  • Other Treatment Options
    • FFP
    • Methylprednisolone starting at 1.5 mg/kg/day and up to 10 mg/kg/day
    • Rituximab, kills specific B cells that are secreting offending antibodies
      • Used in refractory cases but can shorten response time to improvement and decrease relapse risk
    • Platelet transfusion, consultation with Hem/Onc should guide
    • Caplaczumab, binds domain on vWF preventing it interacting with platelets
      • Promising trials with reduction in composite end point of death, recurrence, but increased bleeding

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Hemolytic Uremic Syndrome (HUS)

    • 1.5 persons/100,000 a year
    • 5% mortality, however up to 25% with ongoing kidney problems
    • 90% caused by shiga toxin and mainly affects children 6 months to 4 years

Epidemiology

    • Typical, Shiga toxin bacteria 🡪 damages kidneys directly & damages vascular endothelium and activates platelets and cytokines 🡪 thrombotic microangiopathy
    • Atypical, complement activation 🡪 chronic uncontrolled complement activity 🡪 platelet activation and endothelial damage 🡪 thrombotic microangiopathy

Pathophysiology

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HUS Clinical Presentation

Diarrhea is most common in typical HUS and is often bloody and associated with cramps

Enterohemorrhagic E coli is non-invasive and thus systemic inflammatory symptoms usually absent

Often typical HUS will develop 5-10 days after diarrhea onset

Other Clinical Signs and Symptoms

Renal failure, this is key and is much more prominent in HUS than TTP

    • Decreased UOP, hematuria, HTN, Edema

Neurologic symptoms (confusion and encephalopathy)

Atypical HUS can present with MI, CVA, pancreatitis, liver necrosis

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HUS Diagnosis

  • Made with characteristic lab findings + clinical presentation

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  • Labs: CBC, BMP, hemolysis and coag labs, stool sample
    • Consultants may order screening for specific complement mutations and antibodies associated with atypical HUS

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  • Lab Findings:
    • Thrombocytopenia, anemia, renal dysfunction, INR/PTT nml, high LDH, low haptoglobin, fibrinogen and d-dimer levels normal

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HUS Treatment

    • Supportive treatment (fluids, electrolytes, RBC transfusions, dialysis if needed)
    • Antibiotics are not recommended but controversial
    • Plasma exchange is not effective

Typical HUS

    • Supportive
    • Eculizumab (terminal complement inhibitor)
    • Plasma exchange is considered the most effective tx
    • Platelets should only be transfused if life threatening bleeding

Atypical HUS

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Catastrophic Antiphospholipid Syndrome (CAPS)

  • Very rare, consists of rapid microthrombi development and end organ damage leading to MODs and failure

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  • Pathophysiology via three mechanisms
    • Thrombosis mediated by inhibition of anticoagulant effects of protein C, B2 glycoprotein I
    • Direct activation of endothelial cells and monocytes
    • Direct activation of complement cascade

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  • Triggers: infection, surgery/trauma, malignancy, anticoagulation withdrawal, pregnancy, autoimmune disease flare

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CAPS Clinical Presentation

    • Venous > arterial

Vascular Thrombosis

Pregnancy morbidity

    • Livedo reticularis
    • Cutaneous necrosis, digital gangrene

Skin

    • Renal failure 75%
    • Pulmonary, ARDs in 20%, PE common
    • Neuro: Seizure, encephalopathy, CVA
    • Cardiac: heart failure, MI
    • GI: Bowel infarction

Organ dysfunction

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CAPS Work-Up & Diagnosis

  • Labs
    • CBC, BMP, LFTs, Coags
    • Lupus anticoagulant, anticardiolipin antibody, anti-B2glycoprotein I antibody

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  • Biopsy showing small vessel thrombosis is definitive
    • Often not possible due to clinical condition

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CAPs Treatment

Treat underlying causes

Supportive therapy

    • Including aggressive anti-hypertensive therapy

Unfractionated heparin with high dose steroids

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Hemophagocytic LymphoHistiocytosis (HLH)

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HLH

  • Epidemiology
    • 1 case per million person years, high mortality 50-75%
    • HLH encompasses immune dysregulation due to many stimuli
    • Macrophage activation syndrome (MAS) refers to HLH caused by rheum disease

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  • Pathophysiology
    • Immune hyperactivity involving CD8+ T cells and macrophages 🡪 positive feedback loops mediate 🡪 inflammation rapidly spreads
    • Triggered by inflammatory triggers like infections, malignancy, rheumatologic disease coupled with mutations in an individual's ability to balance inflammation

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HLH Clinical Presentation

Fever occurs in 95%

    • Neuroimaging can show demyelinating lesions, hemorrhage

CNS: delirium to coma, neuro deficits, Has, seizure, PRES

    • All cell lines can be affected
    • Elevated liver enzymes, hypertriglyceridemia, prolonged INR and PTT
    • Elevated inflammatory markers, notably ferritin which is often > 2000 ng/mL

Shock, multiorgan failure including ARDs, AKI

    • Splenomegaly occurs in 70% of patients
    • Hepatomegaly
    • Lymphadenopathy isn’t associated with HLH

Organomegaly

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HLH Work-UP

    • CBC, LFTs, ferritin, fibrinogen, triglycerides (fasting), coags, d-dimer
    • Serum PCR for viral infections (EBV, CMV, HSV), HIV serologies

Labs

    • US of spleen and liver
    • CT pan scan if looking for malignancy

Imaging

    • Looking for hemophagocytosis

Biopsy of involved sites such as bone marrow

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HLH Diagnosis

2009 criteria is more sensitive but less specific.

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HLH Treatment

  • Treat underlying cause (infection, malignancy, rheumatic disease)

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  • Steroids are considered a mainstay
    • Dexamethasone at 10 mg/m2 body surface area daily is one regimen

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  • Other treatments
    • Anakinra, inhibits IL-1 receptors
    • Ruxolitibib, a JAK1 and JAK2 inhibitor
    • Etoposide

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Tissue Lysis Syndrome (TLS)

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TLS

  • Epidemiology
    • The most common oncologic metabolic emergency
    • High morbidity and mortality

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  • Pathophysiology, lysis of large number of cancer cells 🡪 release of intracellular contents
    • DNA ultimately is broken down into uric acid which can cause renal failure
    • Hyperkalemia can cause cardiac dysrhythmias
    • Further complicating hyperkalemia is hypocalcemia secondary to hyperphosphatemia which binds up calcium

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TLS Clinical Presentation

  • Presentation can be nonspecific

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  • Recent chemo and other anti-tumor txs are indicative historical factors, can also be initial presenting sign of hematologic malignancy
    • Often occurs between 6 hours and 7 days after cytotoxic therapy

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  • Significant Complications
    • Renal failure, the most common manifestation
    • Seizures
    • Cardiac dysrhythmias
    • Acidosis
    • Sudden death

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TLS Diagnosis & Work-Up

  • Labs: BMP, uric acid, phosphorous, magnesium, LDH

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  • EKG

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  • Diagnosis w/ Cairo Bishop

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TLS Treatment

IV Fluids

    • Pediatrics <10kg in wt should received 200 ml/kg/day
    • Older children and adults should receive 2-3x maintenance fluids

Hyperkalemia

    • Calcium gluconate 2-4 grams IV via PIV or calcium chloride 1-2g via CVL
    • Regular insulin 5 units IV
    • 50% Dextrose in water (25 grams) 1-2 ampules IV
    • Albuterol 5-10 mg nebulized
    • Sodium Bicarbonate 50 mEq IV

Hyperuricemia

    • Rasburicase 0.2 mg/kg IV ovder 30min q24hr for 5d

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Acute Promyelocytic Leukemia (APL)

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APL

  • Epidemiology
    • 10% of AML patients
    • Affects younger patients, median age 40 years old

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  • Pathophysiology
    • Fusion gene prevents promyelocytes from differentiating into myelocytes
    • Promyelocytes secrete tissue factor and can cause DIC

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APL Clinical Presentation

  • Can be vague
    • Anemia- fatigue and weakness
    • Leukopenia- infections
    • DIC- petechiae, bruising, ICH, pulmonary hemorrhage

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APL Diagnosis & Work-up

  • BMP, Mg, uric acid, CBC, coags, fibrinogen, d-dimer, TEG
    • Thrombocytopenia is often severe
    • PT often prolonged, PTT usually normal
    • Fibrinogen can be low
    • D-dimer often very high unlike other leukemias

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  • EKG, ECHO, CXR as needed

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  • PML/RARA PCR in blood

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APL Treatment

All-trans retinoic acid (ATRA)

    • Allows differentiation to continue
    • Conversion of promyelocytes into neutrophils does release cytokines which can lead to a cytokine storm similar clinically to septic shock

Transfusions, treat if bleeding

    • Platelets > 20k
    • Fibrinogen > 150 mg/dL
    • FFP for target INR 1.5-2

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Blast Crisis

  • Epidemiology
    • 1-6.7% of pts with CML initially present with blast crisis and an additional 1-1.5% pts will progress to this stage
    • Median survival is 7-11 months
    • 5-13% of adult AML patients and 10-30% of ALL patients present with high number of blasts similar to CML blast crisis

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  • Pathophysiology
    • Abnormally active tyrosine kinase protein drives uncontrolled cell growth
    • Blasts proliferate in bone marrow leading to anemia, thrombocytopenia, and immunosuppression (blasts not functioning as mature WBCs)
    • WBC > 100 are at risk for leukostasis

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Blast Crisis Clinical Presentation

  • Constitutional symptoms: fever, night sweats, weight loss, bone pain

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  • Hem/Onc
    • Anemia, thrombocytopenia, bleeding/bruising, petechiae
    • Splenomegaly, lymphadenopathy
    • Can present with TLS and DIC

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  • Pulmonary
    • Ranges from dyspnea to ARDs

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  • Neuro
    • HA, dizziness, visual disturbances, AMS, ataxis, FNDs, ICH, coma

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Blast Crisis Work-up

  • CBC w/ diff, peripheral smear, CMP, uric acid, phos, PT, PTT, fibrin split products, fibrinogen levels, Type and screen
    • Manual platelets counts should be ordered as automated can cause false elevations
    • Cultures if sepsis

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  • CXR
    • Can show infiltrates

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  • If Neuro sx CT

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Blast Crisis Treatment

  • Emergency oncology consultation
    • Goal is induction chemo and/or leukapheresis to rapidly reduce WBC count

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  • IV Fluids can improve hyperleukocytosis

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  • Transfusions
    • Avoid RBCs if possible as this worsens hyperviscosity
    • Platelet goal > 20k

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  • Treat DIC/sepsis/TLS if needed

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References

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Quiz

https://docs.google.com/forms/d/e/1FAIpQLSc_HitPvy2duGmwIs4pqhQCFqm9EPfQ2aMKCzsexp1ROtpF8Q/viewform?usp=sf_link

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