Hematological Emergencies: What every Hospitalist needs to know

Transcription

1 Hematological Emergencies: What every Hospitalist needs to know C. Tom Kouroukis MD MSc FRCPC Juravinski Hospital and Cancer Centre Division of Malignant Hematology Department of Oncology McMaster University September 16, 2016

2 Disclosures InsOtuOonal Research funding Janssen Gilead Sciences Amgen Karyopharm Roche Advisory Boards, Honoraria: None

3 Hematological Emergencies Acute thrombocytopenia TTP and HIT DIC Hyperleukocytosis/Leukostasis & Hyperviscosity Tumour Lysis Syndrome SVC syndrome Febrile Neutropenia Hypercalcemia HLH (hemophagocyoc syndrome) CoagulaOon: hemophiliac bleeding and acquired factor inhibitors

4 Acute thrombocytopenia Normal platelet counts usually x 10 9 /L x 10 9 /L not usually indicaove of disease Spontaneous bleeding not usually seen unless counts < 30 x 10 9 /L Huge differenoal diagnosis and partly depends on whether inpaoent or outpaoent and the rapidity in which platelets have fallen

5 Stasi et al., ASH Hematology 2012

6 Stasi et al., ASH Hematology 2012

7 ITP Usually a diagnosis of exclusion in otherwise healthy adults CBC, blood smear, reocs DAT HIV HepaOOs C Abdo ultrasound Bone marrow opoonal Unlikely to see de-novo severe ITP in hospital

8 Drug induced ITP Huge list of drugs Drug dependent anobodies against epitopes of platelet surface glycoproteins created upon drug exposure Usually 2-3 days or up to 3 weeks depending on prior drug exposure Plts improve 5-10 days acer stopping drug Drug dependent plt anobody tesong not widely available HIT deserves separate menoon

9 Heparin induced thrombocytopenia Immune mediated thrombocytopenia with paradoxical prothrombooc state IgG anobodies to PF4 complexes Cross linking of FC receptors on platelets and monocytes leading to acovaoon and generaoon of thrombin 10 Omes more likely with UFH than LMWH

10 Heparin induced thrombocytopenia HIT occurs in 0.5-5% of heparin exposed subjects Should be suspected if plts fall by >50% while on heparin Median platelet count 50-80, rarely < 20 Clinical: thrombosis, necrooc skin lesions Typically acer 5-10 days of heparin exposure, someomes acer a few hours if prior exposure to heparin (3 months) Occasionally onset is delayed for several days

11 Warkentin, Theodore E. Heparin-induced thrombocytopenia: pathogenesis and management. British Journal of Haematology 121 (4),

12 4Ts pretest probability for HIT Score < 4: NPV 97-99% Score 6-8 points: PPV up to 80% Lo et al., J Thromb Hemost 2006

13 HIT Clinical diagnosis 14 C serotonin release assay is best Immunoassays also available, not bad Cannot wait for tesong if strongly suspected Stop heparin and cover with alternaove anocoagulant (argatroban, danaparoid, bivalirudin, fondaparinux) Careful when starong warfarin?novel oral anocoagulants Avoid giving platelet transfusions

14 ThromboOc Thrombocytopenic Purpura 1924 E. Moschcowitz: 16F abrupt onset of petechiae, anemia, and pallor, followed by paralysis, coma and death. Widespread thromboses in terminal arterioles and hyaline thrombi. hitherto undescribed disease (due to a) powerful poison with both agglu7na7ve and hemoly7c proper7es Courtesy Dr. D. Arnold, McMaster Archives Int Med, 1925

15 TTP: Clinical Diagnosis Pentad Fever (25%) Renal (50%) Neurological (65%) SchistocyOc anemia (100%) Thrombocytopenia (100%) 15 Courtesy Dr. D. Arnold, McMaster

16 Microangiopathic hemolyoc ( schistocyoc ) anemia 16 Courtesy Dr. D. Arnold, McMaster

17 TTP: Facts 4 11 per million (rare) Untreated, 90% fatal (drama7c) Treated, 80% survival (without sequelae) Relapse is expected in 1/3 ADAMTS13 deficiency (year 2000) Treatment is plasma exchange (since 1950 s) Courtesy Dr. D. Arnold, McMaster

18 Clinical AssociaOons Idiopathic TTP ~30% Secondary TTP Pregnancy InfecOon (HIV) Drugs: quinine, Oclopidine, clopidogrel, cyclosporine Autoimmune disorders: SLE, APLA Disseminated malignancy Transplant-associated microangiopathy 18 Courtesy Dr. D. Arnold, McMaster

19 HemolyOc Uremic Syndrome 1. Acute renal failure (often severe) 2. Thrombocytopenia 3. RBC fragments D+ HUS: Clusters (usually) with diarrhea associated with Shiga toxin- producing E. Coli Atypical HUS: Sporadic episodes of HUS, often without diarrhea; increased complement activity 19 Courtesy Dr. D. Arnold, McMaster

20 Ultra-large VWF in TTP Blood Flow Protease Normal Multimers Adhesion, Rolling, Activation, Recruitment No Protease Thrombus Ultra-Large Multimers (TTP?) Courtesy Dr. D. Arnold, McMaster Adapted from Blinder et al

21 Evidence for VWF in TTP 1. Ultralarge VWF mulomers observed 2. Thrombi are rich in VWF and platelets 3. VWF on platelet surface in TTP 21

22 Deficiency of VWF-protease Acute TTP Remission Tsai, NEJM 1998

23 ADAMTS-13 A disintegrin and metalloprotease with thrombospondin type 1 repeats Found in: Liver (perisinusoidal cells), placenta, other Ossues, platelets 23

24 Acquired TTP AnObodies (polyclonal) to ADAMTS-13 Inhibit ac7vity, or increase clearance 24

25 Treatment of TTP 1. Plasma exchange (with plasma) Replacing ADAMTS-13 Removing inhibitors, ULVWF, cytokines, etc. 2. AnA-platelet agents (once platelets> 50) 3. CorAcosteroids, Splenectomy, Rituximab 4. Avoid platelet transfusions 25 Courtesy Dr. D. Arnold, McMaster

26 Rock et al, NEJM 1991 N = Courtesy Dr. D. Arnold, McMaster

27 Refractory TTP (~25%) 1. Continue daily plasma exchange 2. Increase volume of exchange 3. Corticosteroids (1mg/kg prednisone) 4. Immunosuppressants 5. Stay the course 27 Courtesy Dr. D. Arnold, McMaster

28 TTP Take-home messages TTP is a medical emergency, requires prompt recognioon Thrombocytopenia plus schistocyoc anemia Plasma exchange (with plasma) is the mainstay of treatment ADAMTS-13 deficiency (<5%) seen in the majority of TTP, maybe prognosoc for relapse and survival Need to define the role for tesong Alternate immune hypothesis are possible

29 Tumour Lysis Syndrome Biochemical derangements as a result of rapid cancer cell death Hyperuricemia Hyperkalemia Hypocalcemia Hyperphosphatemia Renal impairment

30 Howard et al., NEJM 2011

31 DefiniOons of TLS Metabolic abnormality Laboratory TLS Clinical TLS Hyperuricemia Hyperphosphatemia > 475 umol/l or >25% increase > 1.5 mmol/l or > 25% increase Hyperkalemia > 6.0 mmol/l Cardiac dysrhythmia, sudden death Hypocalcemia < 1.75 mmol/l Or > 25% decrease Cardiac dysrhythmia, sudden death, seizure, neuromuscular irritability, hypotension, CHF Acute kidney injury n/a Increase creaonine > 26.5 umol/l or > 1.5 UNL or oliguria Cairo & Bishop, Br J Haematol 2004; Howard et al., NEJM 2011

32 TLS Typically with hematological malignancies Leukemias and Lymphomas (3-25% incidence) Related to a higher risk of mortality and need for dialysis Related to tumour burden, rapidity of tumour cell growth and effecoveness of treatment Other factors: baseline renal funcoon, fluid status, hypotension, acidic urine

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34 Management of TLS PrevenOon is key if possible OpOmize fluid status and urine output Urine alkalinizaoon may worsen calcium phosphate solubility, so not rouonely recommended Rasburicase and allopurinol are key Phosphate binders (amphogel, sevelamer) Dialysis or cononuous renal replacement Frequent monitoring

35 Hyperviscosity Increase in blood viscosity usually due to pathological increase in plasma proteins or cellular consotuents (WBC, RBC) Symptoms depend on Degree of viscosity Rapidity of viscosity increase Ability to compensate Underlying vascular status and end organ funcoon Typically no symptoms unless viscosity > 4

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37 Causes of hyperviscosity Myeloma IgA more than IgG (IgM myeloma is rare) Typical M protein levels of at least g/l Waldenstroms macroglobulinemia B cell lymphoma that makes IgM Polycythemia rubra vera Hyperleukocytosis Acute leukemia

38 Symptoms and signs Headache Neurological changes Ataxia, verogo Nystagmus Confusion, altered mental state Coma Visual changes Blurring of vision DilataOon/segmentaOon of reonal veins, sausage Central reonal vein occlusion Bleeding

39 InvesOgaOons & Treatment FacOOous hyponatremia Serum protein electrophoresis Total protein, albumin Immunoglobulin levels CBC Look for end organ damage Treat underlying cause Plasmapheresis Avoid transfusions unless absolutely necessary

40 Thomas et al., Br J Opththal 1983

41 Hyperleukocytosis WBC > 100,000/uL Diseases AML ALL CML CLL ComplicaOons usually seen in the sevng of AML or ALL rather than CML and CLL

42 Leukocrit or buffy coat Rollig and Ehninger, Blood 2015

43 Hyperleukocytosis in acute leukemia 10% of acute leukemia paoents have WBC > 100,000/uL AssociaOon with higher LDH, certain cytogeneoc/ morphologic subtypes, poorer ECOG performance status Pathogenesis High leukemic burden with rapid blast proliferaoon DisrupOon of cell adhesion and reduced affinity to the bone marrow

44 ComplicaOons Disseminated intravascular coagulaoon High levels of release of Ossue factor, acovaong extrinsic pathway via factor VII Tumour lysis syndrome Spontaneous or treatment-related cell death Leukostasis Leukemic blast cells are larger and less deformable Mechanical disturbance of blood flow in microcirculaoon Cellular mechanisms and cytokine release TNF, interleukins, adhesion molecules These paoents are higher risk of early mortality and adverse long term outcomes

45 Histopathological findings Rollig and Ehninger, Blood 2015

46 Symptoms of leukostasis Organ Lung CNS Eye Ear Heart Vascular system Symptoms Dyspnea, hypoxemia, alveolar hemorrhage, respiratory failure Confusion, somnolence, dizziness, headache, delirium, coma, focal neurologic deficits Impaired vision, reonal hemorrhage Tinnitus Myocardial infarcoon/ischemia Limb ischemia, renal vein thrombosis, priapism Rollig and Ehninger, Blood 2015

47 Rollig and Ehninger, Blood 2015

48 Treatment Goals of therapy IV hydraoon, allopurinol/rasburicase Check labs and coagulaoon parameters BID unol WBC improved Chemotherapy (hydroxyurea/inducoon) Platelet transfusions (keep > 20-30) Leukapheresis

49 HemophagocyOc Syndrome Also known as hemophagocyoc lymphohisoocytosis (HLH) or macrophage acovaoon syndrome (MAS) Rare, mulosystem disease Unregulated immune acovaoon with cytotoxic T cells, macrophages resulong in cytokine storm and auto-phagy of hematopoieoc cells

50 HemophagocyOc Syndrome

51 HLH treatment HLH 2004 Protocol Steroids Chemotherapy (etoposide) Cyclosporine Intrathecal methotrexate Others: anakinra, IVIG Treat underlying cause (if possible) Allogeneic stem cell transplant

52 Hematological Emergencies Acute thrombocytopenia TTP and HIT DIC Hyperleukocytosis/Leukostasis & Hyperviscosity Tumour Lysis Syndrome SVC syndrome Febrile Neutropenia Hypercalcemia HLH (hemophagocyac syndrome) CoagulaOon: hemophiliac bleeding and acquired factor inhibitors

53 Thank you!