Hematology Flashcards
What is the treatment of Proximal DVT and PE?
Non cancer-associated (DOAC first line, if no contraindications)
– Provoked
* Tx for 3 months (up to 6 months)
– Unprovoked or chronic risk factor
* Tx for 3 - 6 months then assess bleeding risk; continue indefinitely with regular
reassessment of risk:benefit
Cancer-associated (LMWH or DOAC if no contraindications)
– Low/mod bleeding risk: indefinite therapy (1B) while active cancer
(+6 months in remission)
– Anticoagulation: DOAC or LMWH
* If using up front DOAC: must use apixaban or rivaroxaban, edoxaban requires 5d therapeutic
LMWH first
LMWH preferred where bleeding risk is high: high risk GI lesions (e.g. angiodysplasia,
varices), unresected intraluminal GI/GU cancer, high risk intracranial lesion (glioma, RCC,
melanoma), Child-Pugh class B/C, platelet < 50, recent bleed; DOAC Drug Interactions
What are contraindications to DOACS in VTE?
CAUTION IN:
1. Intraluminal GI malignancy not resected, GU (renal/bladder/prostate), ?intracranial malignancy
2. Renal: CrCl < 30 (apix <25; up to <15 but limited data), or dialysis
3. High clot burden: extensive/sub-massive PE, post-thrombolysis, iliofemoral DVT
4. Bariatric surgery: LMWH for first 4 wks–3 months | other malabsorption syndromes = consider LMWH
5. Drug-drug interactions: (eg) amiodarone increases levels of all DOACs [see Thrombosis Canada DDI guide]
2021 UPDATE: Rivaroxaban or Apixaban appropriate for any BMI/weight (except post bariatric sx.)
CONTRAINDICATION IN:
1. Liver failure: Child Pugh B and C
2. Anti-phospholipid antibody syndrome: arterial thrombosis, triple positive, small vessel thrombosis (livedo
reticularis, nephropathy)
3. Pregnancy AND Breastfeeding
4. Drug-drug interactions
(e.g. doxorubicin, cyclosporine, carbamazepine, phenytoin, azoles, protease inhibitors – bleeding risk): apix/riva CYP3A4/P-gp; dabi/edox P-gp)
5. Platelets < 50
DOAC Extension Studies (non-cancer associated)
In unprovoked VTE with low-med bleed risk > 6 mos of full dose treatment, consider lower dose-DOAC.
AMPLIFY – EXT (NEJM 2013)
N= 2482
Apix 5mg BID vs. 2.5 mg BID vs. placebo
Duration 12 mos
EINSTEIN CHOICE (NEJM 2017)
N = 3365
Riva 20mg daily vs. 10mg daily vs. ASA
81mg daily
Duration 12 mos
Caution in:
– Morbid obesity (Wt >120kg)
– Symptomatic pulmonary hypertension
– Index VTE event required thrombolytics
– Active cancer
– Thrombophilia
– Cost – low dose not always covered by drug plans for this indication
When to Use Warfarin for DVT?
“Be CALM”
Breastfeeding
CKD
Antiphospholipid Ab Syndrome
LV Thrombus (+ “Likes warfarin” – pt on warfarin stable for years)
– LV Thrombus (NB observational and 1 small RCT suggests DOAC
may be non inferior to VKA)
Mechanical Valve
– Mechanical valves [INR 2.5-3.5 – mitral, INR 2-3 - aortic]
What is the role of Thrombolysis in VTE?
DVT
- limb-threatening DVT (phlegmasia cerulea dolens)
- ASH: selected younger patients with iliofemoral DVT at high risk of Post thrombotic syndrome
(and low risk for bleeding)
PE
- hemodynamic instability (sBP <90 for over 15 mins) with no high bleeding risk (Gr 2B)
- IV thrombolysis with tPA (not catheter directed)
Bottom line:
Only thrombolyse PEs with hemodynamic instability, not for RV strain or ↑ trop
When do you use IVC filters?
IVC filter only if acute prox DVT (or PE*) & CI to A/C (grade 1B)
What are some complications of IVC filters?
Complications of IVC filters:
* Filter placement – bleeding, infection, malposition of filter, guidewire entrapment
* Post-procedure – DVT, hematoma, AV fistula
* Long-term – filter erosion/migration/embolization, chronic/recurrent VTE
– Filters may decrease risk of PE but increase risk of DVT and have no effect on mortality
When to treat distal DVT?
Severe symptoms, multiple deep veins involved, active cancer, ≥5 cm long, close to popliteal vein, irreversible risk factor, +D-dimer, or progression on repeat U/S
-consider full dose anticoagulation
(treat as proximal DVT)
- If high bleeding risk or no indication to treat monitor with serial U/S
When to treat subsegmental PEs?
Controversial
- Consider treatment if: active cancer/other
thrombotic risk, symptomatic, high D-dimer
When to treat superficial Vien thrombosis?
Superficial Vein Thrombosis:
- ≤3 cm from saphenofemoral junction à full
dose anticoagulation x 3 months
- > 3cm from SFJ and ≥5 cm long à
prophylactic anticoagulation x 45d
(fondaparinux 2.5 mg sc daily or rivaroxaban
10 mg po daily) - > 3cm from SFJ + <5cm long à NSAIDs and
monitor with serial U/S. ** Exceptions:
prophylactic anticoagulation in pregnancy,
cancer, surgery, trauma, prior hx of
SVT/DVT
3 Key points regarding COVID and Thrombosis
Non-hospitalized patients: no routine anticoagulation
– Including patients being discharged home post COVID19 admission = d/c anticoagulants
- Hospitalized non-critically ill: therapeutic intensity anticoagulation (heparin or LMWH
Suggested over prophylactic intensity based on evidence) - Critically ill: prophylactic intensity anticoagulation over intermediate/therapeutic dose
What is the treatment for Vaccine Induced Immune Thrombotic
Thrombocytopenia (VITT)?
No heparin
* Avoid platelet transfusions (unless life-threatening bleeding)
* 1st line anticoagulation: anti-Xa DOACs
* Send HIT ELISA before IVIG
* IVIG 1g/kg actual body weight daily x 2 days
* Consult hematology
Reversal Agents for Anticoagulants
Warfarin
Non-bleeding:
* INR >9: hold warfarin + VitK 2.5-5 mg po
* INR 4.5-9: hold warfarin + decrease dose
Non life-threatening bleed:
* Vit K + supportive
Life threatening bleed/imminent
procedure:
* IV Vit K + prothrombin complex (PCC)
– PCC dosing per INR: INR 1.5-3: PCC 1000U;
INR 3-5: PCC 2000U; INR> 5: PCC 3000U
LMWH
Life threatening bleed:
* Protamine 25-50 mg
Heparin
- Protamine dose based on last admin
DOACs
Non life-threatening: supportive
Life-threatening bleed: supportive +
* Dabigatran:
* Idarucizumab (Praxbind) 2.5g x 2 doses;
consider dialysis (~65% removal in 4 h)
- Apixaban/Rivaroxaban/Edoxaban:
- 4 factor PCC (e.g. Octaplex, Beriplex);
2000U (can be repeated)
Differences between Primary vs secondary hemostasis?
Clinical Presentation - Primary Hemostasis
* Mucocutaneous bleeding
* Easy bruising
* Heavy menstrual bleeding
* Petichiae (low plts)
Labs: +/- ↓ plts, often coags normal
DDx
1. VWF Deficiency
Von Willibrand Disease (VWD)
2. Plt Disorder
↓Quantity -e.g. ITP
↓ Quality -e.g. ASA, uremia, congenital
Secondary Hemostasis
Clinical Presentation:
* Hemarthrosis
* Intramuscular bleeding
* Retroperitoneal bleeding
Labs: abnormal coag. tests
DDx [see slides specific to INR/PTT]
1. Coagulation factor deficiency
* Hemophilia A (Factor VIII)
* Hemophilia B (Factor IX)
* Warfarin (II, VII, IX, X)
2. Coagulation factor inhibitor
* Idiopathic/various diseases
* Medications: DOACs
What is the Approach to Isolated Elevated PT or aPTT ?
Elevated PT (INR)
* Step 1 - rule out pre-analytical error,
medication contamination etc.
* Step 2 = 50:50 mixing study:
A. PT corrects = factor deficiency
* If FVII low (<50%) à factor
deficiency confirmed
* DDx:
congenital/acquired
FVII deficiency, vit K
def., liver disease
B. PT does NOT correct = inhibitor
present
- Check FVII level
- If VII low, check
inhibitor level
Elevated aPTT
* Step 1 - rule out pre-analytical error, medication
contamination Step 2 - 50:50 mixing study 50:50 mixing
study interpretation:
A. aPTT corrects = factor deficiency
– Measure factors VIII, IX, XI, XII (intrinsic
pathway)- 8.9.11.12
* Etiologies: Acquired vs. congenital factor
deficiency vs.VWD
* Confirm by measuring relevant factor
levels (<50% is low)
B. aPTT does NOT correct = inhibitor present
– Lupus anticoagulant (LA) testing
» LA positive - r/o APLA (see rheum lecture)
* Presence of LA is a risk for THROMBOSIS
not bleeding!
» LA negative - factor inhibitor
Measure factors VIII, IX, XI then inhibitor
What is the presentation of VWD?
- Most common bleeding disorder
- ↓quantity or quality of Von Willebrand Factor
- VWF: 1o - plt adhesion and 2o – protects FVIII
Presentation: mucocutaneous bleeding, heavy menstrual bleeding, easy bruising
How do you diagnose VWD?
Diagnosis:
-VWF Ag (quantity), VWF:Ristocetin Cofactor or VWF:GP1bR (VWF activity), FVIII level
* aPTT can be NORMAL in VWD, NOT a good screening test
* VWF :↑ stress, estrogens, pregnancy ; ↓levels in blood group O
Diagnosis (Continued)
* Type 1: Quantitative deficiency (↓VWF:Ag [<30%] = ↓VWF Rco [<30%] ie. concordant; ratio>0.7)
– VWF < 30% or VWF 30-50% + abnormal bleeding = diagnostic
* Type 2: Qualitative deficiency of VWD (↓/↔ VWF Ag [<30-200%], ↓↓VWF:Rco [<30%] ie.
discordant; ratio<0.7)
- Multiple subtypes
* Type 3: No VWF produced (↓VWF:Ag [<5%] = ↓VWF:Rco [<5%]; ↓↓ factor VIII) - Behaves like Hemophilia A
What is the treatment of of VWD?
Treatment:
* Acute Bleeding/Peri-Op: TXA for all
– DDAVP: boosts vWF level (can work for Type 1; not in type 2B/2N or 3)
– Blood products:
* plasma derived concentrates of vWF and FVIII (e.g. Humate P)
What is the work up for ITP?
Definition: Plt < 100 in the absence of other causes
* Presentation: mucosal bleeding, petichiae, wet
purpura
* Workup:
– CBC, blood film, HCV, HIV serology
– Bone marrow biopsy not necessary
– H. pylori – test if eradication therapy would be
used
Treatment for ITP?
Treatment
1) NOT BLEEDING/MILD MUCOCUTANEOUS BLEEDING &
PLT >30
* Watch and wait
2) NOT BLEEDING & PLT < 30
* 1st line: Pred 0.5-2mg/kg or Dex 40 mg X 4d, IVIG
(if C/I to pred; caution: hemolysis), anti-D (RhD+; caution: hemolysis)
– FLIGHT: MMF + steroids
* 2nd line: splenectomy, rituximab, TPO-R agonists
3) ACTIVE BLEEDING
* Steroids + Tranexamic Acid +/- IVIG
* Life threatening: Plt transfusion +/- splenectomy
Myeloid vs. lymphoid disorders
– Myeloid = RBCs, platelets, monocytes, granulocytes
– Lymphoid = B-cells, T-cells
Myeloid Disorders
- Acute Myeloid Leukemia (AML)
– too many immature myeloid cells (i.e. myeloid blasts) - Myeloproliferative Neoplasms (MPNs)
– too many mature myeloid cells
* too many RBCs = Polycythemia vera (PV)
* too many platelets = Essential thrombocytosis (ET)
* too many granulocytes = Chronic Myelogenous Leukemia (CML) - Chronic Myelomonocytic Leukemia (CMML)
– features of BOTH MPN and MDS
* too many monocytes
* myeloid cells are dysplastic - Myelodysplastic Syndrome (MDS)
– not enough myeloid cells (cytopenias) à bone marrow failure
* ineffective hematopoiesis
* myeloid cells are dysplastic
Lymphoid Disorders
- Acute lymphocytic leukemia (ALL)
– too many immature lymphoid cells (i.e. lymphoid blasts) - Lymphoproliferative disorders (LPDs)
– too many mature lymphoid cells
* CLL: burden of disease is in the peripheral blood
* Lymphoma: burden of disease is in lymph node
* Waldenstrom Macroglobulinemia /Lymphoplasmacytic lymphoma - Plasma cell dyscrasias
– Too many plasma cells → overproduction of a single antibody / light chain
* MGUS → smoldering myeloma → multiple myeloma
* Primary amyloidosis
Acute Leukemia (too many immature cells)
Etiology:
* de novo vs. 2o (prior chemo, transformed
MDS,/MPN, congenital d/o (e.g. Fanconi
Anemia, Down Syndrome), benzene)
Presentation:
1. BM failure (loss of normal hematopoiesis)
– Cytopenias:
* Anemia (fatigue), thrombocytopenia
(bleeding), neutropenia (infection)
- Systemic symptoms (due to blasts)
– Leukostasis, DIC, tumor lysis syndrome
– Organ dysfunction
* Skin - rash
* Mucosa - gum hypertrophy
* CNS - Neuro symptoms
Diagnosis:
* ≥ 20% blasts in peripheral blood or marrow*
* WHO classification relies on genetic mutations
* Distinguishing AML from ALL:
– Based on BM biopsy, flow cytometry,
cytogenetics, molecular
– Auer rods only in myeloid neoplasms à
Auer rods never normal
Blast cells + Auer rods + DIC think ?
APL=Acute promyelocytic leukemia
- Subtype of AML
- T(15;17) PML-RARA
- Most curable AML type
- ↑early mortality from DIC:
- Intracranial hemorrhage
- Blood clots
- Urgent treatment: ATRA
all-trans retinoic acid (tretinoin)
Acute Leukemia Associated Emergencies-
Tumor Lysis Syndrome definition and Treatment
- Tumor lysis syndrome
* ↑K, PO4, uric acid (UA), ↓ Ca
* AKI, seizures, arrhythmias
Treatment:
1. Manage hyper-K, correct ext. lytes
2. IVF (target UO 80-100 mL/m2/h)
AND EITHER:
3. Allopurinol
OR
4. Rasburicase if: AKI, ↑↑ uric acid
(>535 umol/L), no response to allopurinol
(NOT in G6PD def)
Acute Leukemia Associated Emergencies-
Leukostasis definition and treatment
- Leukostasis (AML>ALL>CML»CLL):
* Rigid sticky blasts ↓flow → organ dysfunction
* Can affect any/all organ systems
* Lungs (dyspnea/hypoxia)
* CNS (confusion/visual changes)
* In AML if WBC >50-100
* At higher WBC in CML/ALL, rare in CLL
Treatment:
1. IVF
2. Cytoreduction (e.g hydroxyurea, leukapheresis,
induction chemo)
3. TLS prophylaxis
4. Avoid transfusion
Acute Leukemia Associated Emergencies (2)
DIC tx
cytopenias tx
- DIC
Non-APL: - Platelets (see “cytopenias”)
- FFP (15 cc/kg)
* Indication: If bleeding and
PT or PTT > 1.5 x ULN - Fibrinogen concentrate (4g)
* Indication: If bleeding and fibrinogen <1.5
APL: - ATRA
- Platelets (see “cytopenias”)
- Fibrinogen concentrate
* Indication: fibrinogen <1.5 - FFP (15 cc/kg)
* Indication: if bleeding
* No PT/PTT targets unless bleeding - Cytopenias
Platelet transfusion thresholds:
Non-APL:
* No bleeding: plt < 10
* Bleeding: plt < 50
APL:
* Plt < 30-50
Treatment of AML
- Curative intent treatment:
1. Achieve complete remission - How? - induction chemo
- Prevent relapse
- Low risk disease - consolidation chemo
- Int/High risk disease -allo-HSCT
APL subtype
Curative intent treatment:
1. Urgent therapy: All-trans retinoic acid
(ATRA)
– Cause differentiation of APL blasts
– MUST give ASAP if APL suspected
(even before confirmation)
– Reverses coagulopathy
- Treatment: ATRA in combo w/ arsenic
+/- chemo
Treatment of ALL
3 phases of chemotherapy
1. Induction
2. Consolidation/intensification
3. Maintenance
* LONG treatment course (~2 years)
* High risk for CNS involvement so intrathecal chemo +/- rads
* +/- allogenic hematopoietic stem cell transplant
Myeloproliferative Neoplasms (MPNs) definition and examples
Definition: too many mature myeloid cells due to a marrow (clonal/malignant) process
* 4 types that you need to know for RC:
- Chronic Myeloid Leukemia (CML)
-too many granulocytes (neuts, eos, baso) - Polycythemia Vera (PV)
-too many RBCs - Essential Thrombocytosis (ET)
-too many platelets - Primary Myelofibrosis (PMF)
-too much fibrosis (in the bone marrow)
Chronic Myeloid Leukemia (CML)
diagnosis and phases
Diagnosis:
* Peripheral blood PCR for BCR-ABL
(t(9;22) aka “Philadelphia chromosome”)
* Bone marrow biopsy to confirm phase of CML/prognosis (cytogenetics)
* 3 phases: chronic → accelerated → blast
A) Chronic phase CML
* ↑ WBC (mostly neutrophils + its precursors)
* Splenomegaly, mild constitutional sx
* BM + peripheral blasts < 10%
* Peripheral blood: left shift + basos + eos
* Treatment: tyrosine kinase inhibitors (TKI)
(e.g. imatinib), life expectancy ≈ gen population
B) Accelerated phase CML*
* 10-19% blasts in peripheral blood or BM
* Basophils ≥ 20%
* Presence of additional clonal cytogenetic
abnormality in Ph+ cells
C) Blast phase CML
* ≥20% blasts peripheral blood or BM
(= acute leukemia, usually AML, 20-30% ALL),
myeloid sarcoma
* Treatment as per acute leukemia + Tyrosine
Kinase Inhibitors
Polycythemia Vera (PV)
Diagnosis and treatment
Presentation:
* CBC: ↑Hb +/- WBCs +/- PLTs
* Erythromelalgia -triad of redness, warmth, and burning pain, most notably affecting the extremities
aquagenic pruritus
* Arterial / venous thromboembolic complications
Diagnosis: 3 major OR 2 major + 1 minor
Major:
1. Hb > 165/160 g/L (M/F) or HCT > 49%/48% (M/F)
2. BM: hypercellular for age, trilineage growth
3. JAK2 V617F (or JAK2 exon 12) mutation
Minor: Low serum EPO
Risk stratification (for thrombosis)
LOW RISK: Age < 60 and no thrombosis history
HIGH RISK: Age ≥ 60 yo or thrombosis history
Treatment:
EVERYONE: ASA 81 mg (consider BID if CV RFs),
optimize CV risk factors, Hct < 45% with phlebotomy
(CYTO-PV NEJM 2013)
HIGH RISK: cytoreduction with Hydroxyurea
(interferon if young or pregnant)
* Second line: JAK inhibitor (Ruxolitinib) – resistant
/intolerant of Hydroxyurea (RESPONSE trial)
* Venous thrombosis history: anticoagulation
* Arterial thrombosis history: consider ASA BID
Essential Thrombocythemia (ET)
Diagnosis and treatment
Presentation
* CBC: ↑PLTs * Vasomotor sx, thrombosis, bleeding
(acquired VWD with plt ≥ 1000)
Diagnosis: 4 major or first 3 major + minor
Major
1. Sustained ↑ PLT (≥ 450)
2. BMBx: ↑ mature hyperlobulated
megakaryocytes
3. r/o other WHO diseases
4. Presence of JAK2 (50%) or CALR (25%) or MPL
(5%) mutation*
Minor: NO reactive cause
Treatment:
Very low risk (no thrombosis, age<60, JAK2-):
observation
Low risk (no thrombosis, age<60, JAK2+): ASA 81
mg
Intermediate risk (no thrombosis,age≥60, JAK2-):
ASA 81 mg
HIGH RISK (age≥60 and JAK2+ or thrombosis hx):
add hydroxyurea (interferon if young or pregnant)
JAK2+ with CV risk factors -ASA 81 mg BID
*Hold ASA if plt > 1000-1500 or acquired vWD
EVERYONE: optimize CV RFs, monitor new
thrombosis/bleeding
Myelofibrosis (MF)- diagnosis and treatment
Pathophysiology:
Clonal ↑megakaryocytes/granulocytes
→ BM fibrosis → extramedullary
hematopoiesis
- etiology: de novo (primary MF) vs. post-ET/PV
Presentation:
– Massive spleen, early satiety, B symptoms
– CBC: cytopenias
Peripheral blood film:
– Leukoerythroblastic = nucleated RBC +
left-shift
– “Teardrop” RBC cells
– 50% of patients with Budd Chiari have an
MPN
Diagnosis: all 3 major & 1 minor
Major:
- BM: fibrosis, megakaryocyte proliferation, atypia
- JAK2 > CALR > MPL mutation*
- Rule out other MPN/MDS
Minor:
1. Leukoerythroblastic film
2. LDH > ULN
3. Anemia
4. Leukocytosis ≥ 11
5. Palpable splenomegaly
Treatment (based on risk stratification)
Low risk: supportive (e.g. anemia – EPO, danazol)
High risk: allogenic hematopoietic stem cell transplant
For splenomegaly -hydroxyurea, JAK-inhibitors (e.g.
Ruxolitinib), splenectomy
For B Sx -JAK inhibitors
Radiotherapy for extra-medullary hematopoiesis
Chronic Myelomonocytic Leukemia (CMML) diagnosis and tx
Chronic Myelomonocytic Leukemia (CMML)
– features of BOTH MPN and MDS
* too many monocytes
* myeloid cells are dysplastic
Diagnosis:
– Peripheral blood monocytosis ≥ 1 x 109/L and ≥ 10% of total WBC for >3mo
– Blasts <20% (blasts ≥ 20% = acute leukemia)
– Exclusion of other MPN (e.g. CML, ET, PV)
– Supporting criteria: dysplasia, cytogenetic/molecular abn, partitioning of monocyte subsets
Prognosis:
– 15-30% get AML
– Most important prognostic factor = % blasts
Treatment:
– Dysplasia: treat as MDS
– Proliferative: treat as MPN
CLL - Diagnosis and Treatment
Presentation:
* Older pt, well, isolated ↑WBC (lymphocytes)
* Peripheral blood: ++ small mature lymphocytes
& “smudge” cells
Diagnosis:
* peripheral blood flow cytometry
* peripheral blood CLONAL B-cell lymphocyte
count ≥5 *Do not need BMBx to make dx
Complications:
* Lymphadenopathy / splenomegaly
* Cytopenias :
– Crowding in marrow and/or autoimmune
disorders (ITP / AIHA)
* Richters transformation -sudden ↑LN size -
aggressive lymphoma (DLBCL)
* Secondary malignancies
Treatment:
* If asymptomatic: watch & wait
– Ensure vaccines up to date, avoid LIVE vaccines
- Indications for treatment
– Lymphadenopathy > 10 cm or symptomatic
– Splenomegaly > 6 cm below CM or
symptomatic
– Progressive cytopenias - BM failure
(Hb < 100, plts < 100)
– AIHA/ITP with poor steroid response
– Extranodal involvement
(skin, lung, kidney, spine)
– Significant constitutional symptoms
– Treatment choices based on pt values,
disease risk stratification - Chemoimmunotherapy (FCR, V-O) vs.
tyrosine kinase inhibitors i.e. Ibrutinib (SE =bleeding, A.fib)
History/Workup for Lymphoma
Risk factors:
* Infections
– HIV (Hodgkin’s, NHL: DLBCL, CNS lymphoma, Burkitt, effusion lymphoma)
– EBV (Burkitt’s)
– H. pylori (gastric MALT)
– C. psittaci (ocular MALT)
– Hepatitis C (NHL)
* Immunosuppression : Post-transplant lymphoproliferative disease (PTLD), ↑ risk with
certain DMARDs and biologics
* Chronic inflammation: Sjögren’s (salivary gland MALT), Celiac or Crohn’s (GI lymphoma),
SLE & RA associated with NHL
B-symptoms:
- Weight loss (>10% in 6 mo)
- Unexplained fevers (>38.3 0C x ≥2 weeks, no infection)
- Night sweats
Diagnosis: – NEED EXCISIONAL LYMPH NODE BIOPSY FOR DIAGNOSIS
Lymphoma Staging/Prognosis
Staging:
* (PET)-CT neck/chest/abdo/pelvis
* BMBx/aspirate
* +/-LP
* Ann-Arbor Staging System (older)
* Stage 1: Single lymph node region
* Stage 2: Lymph node regions on the same side of
the diaphragm
* Stage 3: Lymph node regions on both sides of the
diaphragm
* Stage 4: One or more extralymphatic organs
(includes bone marrow)
* A: no symptoms; B: B-symptoms; E: contiguous
extranodal site; S: splenic involvement
Work up for Plasma cell dyscrasias
- Protein electrophoresis
* Serum (SPEP) and 24 hr urine (UPEP) - Immunofixation
* Qualitative: determine “type” of
M-protein (eg: IgG /IgA/IgM, k vs. λ) - Serum free light chain (FLC) assay
* Normally k & λ light chains present in ~ equal amount
» k : λ ratio varies around 1 (0.26-1.65)
» Free light chains filtered by kidney but resorbed
» Monoclonal excess light chains supercede resorption capacity à
urinary excretion
* Renal failure (not MM): ↓light chain excretion, k ↑ ↑, λ ↑
» E.g. k : λ ratio ~2
* Myeloma: clonal FLC will skew ratio
» E.g. IgG-k myeloma → k : λ ratio = 35 - BMBx, aspirate
* Plasma cell burden; normally <1%
* Prove clonality (flow cytometry)
* Cytogenetics (risk stratify myeloma) - Other tests: Blood film (rouleaux), serum immunoglobulins,
albumin and beta-2-microglobulin (prognostic)
Imaging for Plasma cell dyscrasias
- Imaging
Low Risk MGUS: no imaging needed
High Risk MGUS: low dose whole body CT (more sensitive than skeletal survey)
* if IgM – no bone imaging, do CT abdo/pelvis
Solitary Plasmacytoma: PET/CT or MRI
Smoldering Myeloma: low dose whole body CT
Myeloma: low dose whole body CT or PET/CT
The MGUS-Myeloma Spectrum IMWG 2014 Criteria
MGUS
M-spike < 30 g/L
-&-
BM plasma cells < 10%
-&-
No SLiM CRAB (see next slide)
Smoldering
Myeloma
M-spike ≥ 30 g/L
-&/or-
UPEP-spike ≥ 500 mg/24h
-&/or-
BM plasma cells 10-60%
-&-
No SLiM CRAB or
Amyloidosis
Multiple
Myeloma
BM plasma cells ≥ 10% or
Extramedullary plasmacytoma
-& either-
Biomarkers of malignancy
(SLiM)
-or-
End organ damage (CRAB)
Myeloma - Diagnosis
BM plasma cells ≥ 10% or plasmacytoma AND any SLiM CRAB = myeloma
Sixty: BM clonal plasma cells ≥60%
Light chains: Involved / uninvolved FLC ratio ≥ 100, involved light chain should be >100mg/L
MRI: > 1 focal bone lesions that are ≥ 5 mm on MRI
[Ca2+ ]: > 2.75 or > 0.25 mmol/L above ULN
Renal: Cr > 177 μmol/L or CrCl < 40 (attributable to MM)
Anemia: Hb < 100 g/L or 20g/L below the LLN
Bone: ≥ 1 osteolytic lesion (skeletal survey, CT or PET/CT)
Management- MGUS
High Risk (any 1 of):
1. M-protein ≥ 15 g/L
2. Non-IgG M-protein
3. Abnormal free light chain (FLC) ratio
Low risk MGUS: 2% risk of transform’n @ 20y -no
BM biopsy/bone imaging -CBC, SPEP, FLC, Ca, Cr in 6 mo -if stable FU if new symptoms or q2-3y
High risk MGUS: >20% risk of transform’n @20 yrs
-BMBx, whole body CT, CT abdo if IgM -CBC, SPEP, FLC, Ca/Cr in 6 mon–> stable -rpt q1y lifelong
Smoldering Myeloma Management
Smoldering Myeloma
* BM biopsy/aspirate & imaging to rule out bony
lesions (CT or MRI) - rule out MM
* If no MM - monitor closely
(+ annual re-imaging)
Myeloma Management
Myeloma:
* No cure
* Transplant (auto-HSCT) eligible (~≤70 yo, fit):
chemo à auto-HSCT à maintenance therapy
* Transplant ineligible: chemo maintenance therapy
AL (Light Chain) Amyloidosis- definition and diagnosis
Definition: Plasma cell dyscrasia (or lymphoma) with secondary monoclonal light chain deposition
in organs (e.g. renal, cardiac, liver, peripheral nerves, GI, soft tissue infiltration, coagulopathy)
Diagnosis
- Clonal plasma cell disorder (eg: evidence of M protein or abnormal FLC or clonal
plasma cells in BM) - Presence of amyloid related systemic syndrome (eg renal, cardiac, GI, liver, neuropathy)
- Amyloid on bone marrow or tissue biopsy -“apple green birefringence” on Congo red
stain - Prove amyloid is light chain restricted (mass-spectrometry or electron microscopy)
Treatment: Similar to myeloma
Waldenstrom’s Macroglobulinemia definition and diagnosis Definition:
Definition:
1. Lymphoplasmacytic lymphoma
(an indolent lymphoma with features
between B-cells & plasma cells)
AND
2. Monoclonal IgM in the peripheral blood
Presentation:
1. Symptoms 2o to infiltration
→ Anemia (BM infiltration), (order CT Abdo)
hepatosplenomegaly, lymphadenopathy
- Symptoms 2o to autoimmune processes
→ Neuropathy
-Autoimmune hemolytic anemia
- Cold agglutinin disease - Symptoms 2o to monoclonal IgM:
→ Type I cryoglobulinemia
→ Hyperviscosity syndrome
– Headaches, neurologic symptoms,
mucocutaneous bleeding
-Bleeding
Management:
– Treat when symptomatic
– PLEX for hyperviscosity syndrome
(removes serum IgM)
– Chemoimmunotherapy with rituximab
Myelodysplastic Syndrome (MDS)
Pathophysiology:
* Clonal, dysplastic cells - dysfunctional blood cells à
risk of progression to AML * Etiology: idiopathic vs 2o to DNA damage
(rads/chemo/hydrocarbons)
Presentation:
* Older pt. w/ a cytopenia (often ↓Hb + ↑MCV)
* Blood film: hypolobated/hypogranular neutrophils,
hypogranular platelets, macrocytosis, ↓ retics
Risk stratification (IPSS-M): - based on:
1) Clinical 2) cytogenetics 3) Molecular
Treatment
* Low risk:
– Supportive (EPO, transfusions, Fe chelation)
– Lenalidomide (5q deletion), immunosuppression,
luspatercept (ringed sideroblasts)
* High risk:
– Supportive (EPO, transfusions)
– Cure: allogenic stem cell transplant
– Ineligible for transplant: hypomethylating agents
(azacitidine)
Aplastic Anemia (AA)
Definition: stem cell disorder, ↓blood cell
production and ↓ marrow cellularity
Presentation: Previously healthy pt with
pancytopenia, low reticulocytes, +/- ↑LFTs
Etiology:
– Idiopathic
– Congenital BM failure syndromes
– 2o: pregnancy, autoimmune disease,
drugs (NSAIDs, propylthiouracil,
carbamazepine)
Diagnosis
* BM biopsy: hypocellular (<25%)
* Severe: ANC <0.5, Plt <20, Retics <60
Treatment
– Required for severe AA
– Supportive transfusion (irradiated),
immunosuppression (CsA + anti-
thymocyte globulin (ATG) or allo-
hematopoietic stem cell transplant
(HSCT)
– If drug-related: may obtain remission
with cessation of drug alone
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Definition:
Clonal stem cell disorder characterized by:
1. Bone marrow failure
2. Chronic intravascular (+extravascular)
hemolysis à uncontrolled complement
activation
3. Thrombosis (venous + arterial) - common
site = splanchnic, hepatic
Presentation: thrombosis in atypical locations
(ie. abdominal or cerebral veins), anemia Sx,
hemolysis Sx (jaundice, red urine), pHTN Sx, Sx
from decreased Nitric Oxide (erectile dysfxn)
Work-up
* Hemoglobinuria (rare), hemolysis labs, Cr
(renal failure from pigment nephropathy)
Diagnosis
* Peripheral blood flow cytometry
(loss of CD55 + CD59)
* Overlap w/ aplastic anemia à if pancytopenia
à perform BM biopsy/aspirate
Treatment
* Anti-coagulate if thrombotic events
– No role for primary prophylactic anticoagulation
* Eculizumab or pegcetacoplan (complement
inhibitors) à
↓ hemolysis + transfusion need (not curative)
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Heparin-induced Thrombocytopenia
Management of HIT:
Anticoagulant Choice:
- IV: Argatroban, Danaparoid
- SC: Fondaparinux
* <50 kg→5 mg SC daily
* 50-100 kg→7.5 mg SC daily
* >100 kg→10 mg SC daily
* CrCl 30–50 ml/min→ caution
* CrCl <30 ml/min→ do not use
- PO: Warfarin, DOACs
- Warfarin: start when PLT ≥ 150 + overlap with non-
heparin anticoagulation ≥5d once INR 2 – 3
- DOACS (rivaroxaban 15 BID x 3 wks if VTE or until plt recovery if no VTE - Rivaroxaban 20 mg daily
- Pregnancy: Danaparoid preferred
Duration:
- No thrombosis = min. until platelet recovery (>150), max 3 mon
- Thrombosis = 3-6 mn
Bilateral Leg Dopplers: r/o silent DVT in all pts
Upper Extremity Dopplers: only if UE central venous line in situ
Platelet Transfusion: AVOID
Thrombotic Microangiopathy (TMA)
- Schistocytes (aka fragments) on blood film: think TMA!
- TMA =
– Micro-angiopathic hemolytic anemia (MAHA) à schistocytes
– ↓Plt
– Microvascular thrombi à end organ damage
Primary TMA
- TTP (ADAMTS13 deficiency)
– Congenital vs acquired - Atypical HUS (complement mediated)
– Congenital vs acquired - HUS (Shiga toxin) adult «_space;peds
2.Secondary TMA
- Preg: pre-eclampsia/eclampsia, HELLP
- Malignancy
- Infection: HIV, HepC, H1N1, etc.
- Malignant HTN
- Autoimmune: scleroderma renal crisis,
APLA, SLE, vasculitis - Transplant (BMT + solid organ) associated
- DIC
- Drug associated (cocaine, calcineurin
inhibitors, VEGF inhibitors)
For RC, treat all TMAs as TTP until proven otherwise
Thrombotic thrombocytopenic purpura (TTP)- A Hematologic Emergency
- ↓ADAMTS13 → ↑ big VWF → plts aggregate → + + micro-thrombi
- Mortality: no treatment >90%, with treatment 10 – 20%
- Classic penTAD is a TAD too late! (only 5% have all 5)
- ↓ plt, hemolytic anemia, fever, neuro sx, renal failure
- Only require first 2 to make the diagnosis
- Work-up:
- ADAMTS13 level (send before FFP/PLEX; do not wait for result)
- R/O other causes of TMA
- PTT and INR will be normal
- ↑ trop (TnI>0.25) => 3X death/refractory disease
Treatment:
–PLEX within 4-8h
* FFP to bridge: 3-4u then 1u q2h
–No plt transfusion unless life-threatening bleed
–Steroids (Pred 1 mg/kg/d or Solumedrol IV 1g/day)
–Folic acid 5 mg daily
–+/- ASA if ↑ trop/CNS symptoms once platelets >50
–DVT proph when plt >50
–Caplacizumab or Rituximab can be considered in refractory cases
Hemolytic Anemia Approach
Based on why the hemolysis occurs
1) Intrinsic RBC issues
– Membrane defect: hereditary elliptocytosis / spherocytosis
– Enzyme defect: G6PD deficiency
– Hemoglobinopathy: thalassemia, sickle cell
– Complement-mediated: PNH
2) Immune-mediated
– Autoimmune (warm/cold)
– Alloimmune (i.e. hemolytic transfusion reaction)
3) Mechanical
– TMA
– Mechanical heart valves
4) Other
– Malaria, wilson’s disease
Warm Autoimmune Hemolytic Anemia
IgG-mediated - reticuloendothelial system - hemolysis at body temp
Diagnosis:
- Hemolysis labs
- Blood film: spherocytes
- DAT: +IgG (+/- C3d)
Etiology: 1o vs 2o
– 2o: Lymphoproliferative disease (e.g. CLL),
autoimmune (e.g. SLE), drugs
(e.g. methyldopa, NSAIDs)
Treatment:
1st line: Prednisone 1 – 1.5 mg/kg/day
2nd line:
- Splenectomy (>8-12 mon)
- Rituximab
Supportive:
Folic acid, transfuse for symptoms (requires
investigations - call blood bank)
Cold Autoimmune Hemolytic Anemia
IgM fixes complement - intravascular hemolysis at temp < 37
Diagnosis:
– Hemolysis labs
– Blood film: agglutination
– DAT +ve C3d (= IgM antibody)
– Thermal amplitude: significant if ≥28
Etiology: 1o vs 2o
– 2o: Infection (mycoplasma pneumonia,
EBV), lymphoproliferative disorder
(MGUS, Waldenstroms, lymphoma)
Treatment:
– #1: Warm patient!
– Treat underlying cause
– Steroids not helpful
– Rituximab for refractory cases
Iron Deficiency Anemia
Signs & Symptoms:
anemia-related, restless legs, pica, fatigue,
glossitis, koilonychia
* Blood film:
microcytosis, hypochromia,
pencil cells, targets cells, ↑plt
* Diagnosis:
Ferritin <30
Ferritin >30 + Tsat <20% + inc. TIBC
sTFR ↑
Treatment:
– Identify & treat etiology of Fe loss
– Treat if Ferritin <50 in pregnancy
PO
– Ferrous fumarate: 100 mg Fe – Ferrous sulfate: 60 mg Fe– Ferrous gluconate: 30 mg Fe – Daily vs. q2d – Continue for 3 months after ferritin normalizes
IV
– Who?
* Mod/severe iron def. anemia (Hb <80-100)
* No response/intolerance to oral * Limited time (e.g. pre-op or pregnancy <1 mon
from OR/delivery)
– What?
* Iron sucrose (e.g. 300 mg IV x 3)
– Caution: limited evidence in 1st trimester
* Monoferric (e.g. 1g IV x 1) – Caution: little evidence in pregnancy, avoid if known drug all
– How much?
* Ganzoni equation to calculate Fe deficit
Transfusion Reaction Differentials: Symptom-based
1) Fever (+/- chills, rigors)
– Febrile non-hemolytic transfusion rxn (FNHTR)
(most common)
– Sepsis (bacterial contamination)
– Acute hemolytic transfusion rxn (AHTR)
2) Hypotension
- Sepsis (bacterial contamination)
- Acute Hemolytic Transfusion Reaction
- Anaphylaxis
- TRALI
- Bradykinin-mediated
* No fever or allergy
* 50% of patients on ACE-inhibitor
3) Dyspnea
- Transfusion Associated Cardiac Overload (TACO)
- Transfusion Related Acute Lung Injury (TRALI)
- Anaphylaxis
4) Urticaria/Allergic reaction
- Urticarial → anaphylaxis
5) Delayed cytopenias
- RBC: delayed hemolytic transfusion rxn
- PLT: post-transfusion purpura (PTP)
- All lineages + fever, rash, diarrhea
→ transfusion-associated graft vs. host disease
Transfusion Reactions – Low Risk Situations
1) Febrile non-hemolytic transfusion reaction (FNHTR)
– Temperature ≤ 39o + no other concerning features
– Due to (A) pyrogens in product
(B) recipient Abs vs. donor WBCs
– When fever develops: stop, assess patient, check for clerical error
– If no concerning features, give acetaminophen & slowly re-start
2) Urticaria
– Stop, assess patient, check for clerical error
– If < 2/3 body surface area + no other concerning features
– Give Benadryl & slowly re-start
*Concerning features – hypotension, tachycardia, rigors/chills,
anxiety, dyspnea, back/chest pain, bleeding from IV sites, N/V
**Abort transfusion in all other scenarios
Sickle Cell -presentation
Complications by mechanism:
1) Anemia/ischemic perfusion injury: VasoOcclusive pain
Events (VOE), CVA, ACS, AVN, sequestration, retinopathy,
osteoporosis, asplenia
2) Hemolysis: priaprism, pulmHTN, ulcers, cholelithiasis
Both: nephropathy, VTE, hepatopathy
Pillars of outpatient treatment:
1) General medical care: vaccination (asplenia), VOE pain
mgmt. plan, complications screening (CBC, retic, hepatic
chemistry, renal chemistry, urinalysis, MRI brain,
retinopathy screen, TTE, BMD, x-ray joints, PFT)
2) Therapies (with approval):
* Hydroxyurea (↓VOC, ↓ACS, ↓transfusions, ↑survival,
↓ hospitalizations)
* Exchange transfusion
Sickle Cell Disease- treatment
Helpful inpatient Investigations:
– CBC/retic
– Hb electrophoresis
– Chemistries, Troponin, BNP, lactate
– Group and screen – blood bank to phenotype
blood (and consider genotyping)
- Vasoocclusive crisis:
– Rapid (1hr) analgesia with
acetaminophen/NSAID/hydromorphone
standing + prn, adjuncts ketamine/regional
anesthesia
Acute chest syndrome: clinical diagnosis
– Defn: New infiltrate + new symptom (fever,
hypoxemia, tachypnea, chest pain, cough,
wheeze)
– Triggers: fluid overload, pulmonary infection,
PE, fat embolism, intravascular pulmonary
sequestration of sickled erythrocytes
* 50% of sickle cell patients will develop ACS AFTER
they were admitted
– Treatment: IVF, analgesia, oxygen, incentive
spirometry, Abx, ± transfusion (simple vs.
exchange guided by clinical picture and sickle
cell parameters)
Transfusion in Sickle Cell Disease
Exchange Transfusion
* Severe acute chest syndrome (multi-organ failure)
* Acute ischemic stroke
* Secondary stroke prophylaxis
* Primary stroke prophylaxis (if high-flow transcranial
doppler US)
* Pre-operative if high-risk procedure, Progressive
cholestasis, Post-solid organ transplant, High-risk
pregnancy, other SCD complications (pulmonary
hypertension, priapism, renal disease, ulcers),
complications despite top-op transfusion, prevention of
pain crises/ACS if failed HU
* Patients needing top-up if Hb >90
Simple (Top Up) Transfusion
* Hemoglobin <50g/L unless
from hyperhemolysis
* Mild-moderate acute chest
syndrome
* Pre-operative prophylaxis in
patients with Hb <90
undergoing low-moderate risk
surgery
Blood Product “Modification”
Indications for irradiated blood - prevent transfusion associated GVHD:
-Intra-uterine or neonatal exchange transfusion.
- Congenital T-cell immunodeficiency.
- Autologous stem cell transplant recipients until 3mo post-transplant
- Allogeneic stem cell transplant until at least 6 months post-transplant (indefinite if
GVHD or on immunosuppression)
- CAR-T cell until 3mo post-infusion
- All patients with Hodgkin’s Disease.
-T-cell depleting therapies
Indications for washed platelets:
-Anaphylaxis to transfusion NYD
-Recurrent/severe allergic transfusion reactions
-IgA deficiency with no IgA deficient donor available
Vitamin B12 deficiency
Etiology: - Dietary deficiency (vegans) or meds (PPI, H2 blocker, metformin)
- Absorption issues - no intrinsic factor (pernicious anemia)
- Atrophic gastritis or Pancreatic insufficiency or Terminal ileum disease
Clinical manifestations:
– Anemia-related symptoms, mild jaundice
– Glossitis
– Neurological: subacute combined degeneration (posterior columns & corticospinal tract),
peripheral neuropathy, dementia
Hematologic: - CBC: macrocytic anemia, other lines can be decreased
- film: oval macrocytes, hypersegmented (≥ 5 lobes) neutrophils
* Associated Labs: - low B12, elevated methylmalonic acid & homocysteine levels
- Anti-intrinsic factor and anti-parietal cell antibodies (pernicious anemia)
* Treatment:
* Daily high-dose (≥ 1000 μg) oral B12 is as effective as intramuscular supplementation. Hematologic
abnormalities should resolve within weeks and neuropsychiatric symptoms within months
* If profound deficiency and need to urgently replace (eg in pregnancy w symptoms) - Vitamin B12
1000 mcg IM daily x7d, then 1000mcg qweek x4, then 1000mcg IM q1month lifelong
* OR once replete, vitamin B12 1000-2000 mcg po OD
B12 deficiency or syphilis?
Distinguish Neuro B12 deficiency from Neuro Syphilis
– BOTH: Mental status changes/Dementia
– Pupils: B12: Normal Syphilis: Argyle Robertson
– B12 = subacute combined degeneration of cord = corticospinal tract
(UMN weakness, increased tone in legs, hyperreflexia/clonus) AND
dorsal column (dec. vibration, proprioception)
– Syphilis = “Tabes Dorsalis” = dorsal column (vibration, proprioception
impaired) and dorsal roots (absent reflexes in LE). Unlike B12 deficiency,
tone/power should be normal.
Pre-test Probability for VTE
Well’s Score for DVT (1 pt. for each) not tested in pregnancy
History - Active CA (≤6 mo)
- recent lower limb immobilization
- recently bedridden > 3d or surgery (w/in 4 wk)
Physical Exam - tenderness along deep veins
- evident collateral veins
- entire leg swollen
- calf swelling > 3cm (10 cm below tib tub.)
- pitting edema
- non varicose superficial veins
- Minus 2 for likely alternative diagnosis
Modified Well’s Score for PE
4 History - active cancer (1)
- hemoptysis (1)
- prior VTE (1.5)
- recently bedridden or surgery (1.5)
2 Physical Exam - symptoms of DVT (3)
- tachycardia (1.5)
- No alternative diagnosis (3)
Beta Thalassemia
Etiology
* Absent or reduced globin gene production
* b-thal subtypes: minor/intermedia/major;
clinically, more important whether
transfusion-dependent
Clinical manifestations/complications
* Ineffective erythropoiesis
* Extramedullary hematopoiesis (skeletal
changes, hepatosplenomegaly)
* Hemolysis: anemia, gallstones
* Iron overload: both from ineffective
erythropoiesis + transfusion support
Treatment:
* Paradigm moving from major/intermedia
to transfusion dependent/non-
transfusion-dependent thalassemia;
transfusion-dependency based on
anemia + complications
* Ferritin measurement q3months,
liver/cardiac MRI for iron quantitation
* Iron chelation for features of iron
overload (significant toxicities/details of
chelators beyond GIM exam)
* Consideration of splenectomy
* Many novel therapeutics on horizon
