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What I Think I Know About Hematology in 2015
Robert C. Langan, MD, FAAFPProgram Director
St. Luke’s Family Medicine ResidencyBethlehem, PA
DISCLOSURE: Neither I nor my family have any financial interest or relationship with any proprietary
entity producing health care goods or services
OBJECTIVES
At the conclusion of this presentation, you should be able to:
1. Describe the primary care management of common abnormalities of white blood cells
2. Describe the primary care management of common abnormalities of red blood cells
3. Describe the primary care management of common abnormalities of platelets
4. Review common questions regarding the new oral anticoagulants
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Leukocytosis Pearls
DIFFERENTIATION
BANDPMN
EOSINOPHIL BASOPHILMONOCYTE
LYMPHOCYTE
• NEUTROPHILS: – Most numerous, phagocytose bacteria, first response
• EOSINOPHILS: – Release toxins, fight parasites, allergic reactions
• MONOCYTES:– Largest WBC, macrophages, phagocytose, clean up an inflammatory response
• BASOPHILS– Aid in inflammatory response, contain heparin/histamine, least numerous
• LYMPHOCYTES:– Produce antibodies (B‐cells), cell‐mediated immunity (T‐cells)
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LEUKOCYTOSIS (WBC >11,000)
• NEUTROPHILIA: Infection (“left shift”), inflammation, stress response, drug response, asplenia
• EOSINOPHILIA: Allergic reaction, parasitic infection
• MONOCYTOSIS: TB or connective tissue disease
• BASOPHILIA: viral infections, inflammatory conditions
• LYMPHOCYTOSIS: EBV, CMV, pertussis, TB, asplenia
Davis AS, Viera AJ, Mead MD. Leukemia: an overview for primary care. Am FamPhysician 2014;89(9):731‐8.
When to Obtain a Peripheral Smear
• Persistent leukocytosis (> 3 months)
• WBC >20,000 cells/mL
• Associated anemia, thrombocytopenia, thrombocytosis
• Hepatomegaly, splenomegaly, lymphadenopathy
• Fever, fatigue, weight loss
Interpreting Peripheral Smear with Leukocytosis
• Note associated anemia and thrombocytopenia
• ↑ Atypical Lymphocytes: EBV, CMV, HIV
• ↑ Increased Hematopoietic Cells– Increased blasts: AML vs. ALL
– Few blasts, ↑ basophils/eosinophila: CML
• >50% Normal Lymphocytes:– Flow cytometry to r/o CLL
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Acute Leukemia
• Predominance of blast cells on peripheral smear
• Immunophenotyping by flow cytometry for diagnosis
• Acute Myeloid Leukemia (AML)– 80% of acute leukemia in adults
– Auer rods, hepatosplenomegaly uncommonly seen
– Fever, lethargy, bleeding/bruising
• Acute Lymphocytic Leukemia (ALL)– Most common leukemia in children
– Commonly have hepatosplenomegaly, fatigue, bleeding/bruising
Davis AS, Viera AJ, Mead MD. Leukemia: an overview for primary care. Am Fam Physician 2014;89(9):731‐8.
Chronic Leukemia
• Almost exclusively diseases of adults
• Often WBC >100,000 cells/mL
• Often an incidental diagnosis
• Chronic Myeloid Leukemia (CML)– Philadelphia chromosome (translocation between chromosomes 9 and 22) for diagnosis
• Chronic Lymphocytic Leukemia (CLL)– Common in older adults
– Diagnosis by >5000 B lymphocytes on flow cytometry
Davis AS, Viera AJ, Mead MD. Leukemia: an overview for primary care. Am FamPhysician 2014;89(9):731‐8.
NEUTROPENIA
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Neutropenia Pearls
• Acute neutropenia (<3 months) common
• Cause usually external to bone marrow
• Infection: CMV, EBV, TB, Lyme
• Drugs: anti‐thyroid medications, ticlodipine, clozapine, TMP‐SMX, sulfasalazine, rituximab, alcohol
• MILD (1500‐1000): repeat CBC in 3‐4 weeks
• MODERATE (500‐1000): bone marrow bx, frequent CBC
• SEVERE (<500): ↑ risk of infection, bone marrow
Boxer LA. How to approach neutropenia. Hematology Am Soc Hematol;2012:174‐182.
Neutropenia Pearls
• Neutropenic fever causes ½ of cancer deaths from lymphoma, leukemia, and solid tumors
• Defined as absolute neutrophil count (ANC) <500 cells/mm3 (bands + neutrophils x WBC x 10)
• Fever:
– is single oral temperature ≥38.3° C (101° F) OR
oral temperature ≥38° C (100.4° F) lasting for 1 hour
Neutropenia Pearls
• Differentiate low risk patients from high risk patients using the Multinational Association for Supportive Care in Cancer (MASCC) Risk Index Score
• http://www.qxmd.com/calculate‐online/hematology/febrile‐neutropenia‐mascc
• Low risk patients may be treated in an ambulatory setting with close follow up
• High risk patients must be admitted, start broad spectrum antibiotics and look for source of infection
• IDSA Guideline (2011): http://www.idsociety.org/uploadedFiles/IDSA/Guidelines‐Patient_Care/PDF_Library/FN.pdf
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Polycythemia Pearls
Polycythemia Pearls
• Primary Polycythemia (Polycythemia Vera)
– Very rare, associated with leukocytosis, thrombocytosis, splenomegaly
– Serial phlebotomy, medical therapy
– Higher risk of VTE
• Secondary Polycythemia
– More common
– Due to increased production of erythropoietin
– COPD, HF, OSA, pulmonary hypertension, high altitude
Anemia Pearls
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Iron Deficiency Anemia Pearls
‐Most common form of anemia‐Pallor is an unreliable finding‐Ferritin is the most accurate confirmatory test
‐<30 ng/mL has a sensitivity of 92%, specificity of 98%
‐Replace with oral iron (325 mg FeSO4 TID); SE of constipation, black stools, + hemoccult test
‐Absorption ↑ with acidic environment, vitamin C‐Reticulocyte count responds first (1‐2 weeks), then HGB; follow CBC monthly; continue iron x3 months after CBC normal
Iron Deficiency Anemia Pearls
Iron Deficiency Anemia in adults may be due to:‐Uterine bleeding (20‐30%)*‐NSAID/ASA related gastritis (10‐15%)**‐GI malignancy (5‐10%)‐Celiac disease (4‐6%)‐Urinary tract disease (uncommon)
*Most common cause in menstruating women**Most common cause in men, PMP women
Killip S, Bennett JM, Chambers MD. Iron deficiency anemia. Am Fam Physician 2007;75:671‐8.
B12 Deficiency Anemia Pearls‐Cobalamin (vitamin B12) deficiency (<200 pg/mL) may produce a macrocytic anemia
‐More common than folate deficiency
‐Elevated methylmalonic and homocysteine (useful in patients with low‐normal B12 levels)
‐Can be seen with metformin, H2 blockers, PPI, IBD, vegetarians, alcoholics, pernicious anemia
‐Oral replacement (1‐2 mg/day) as effective as IM replacement (1 mg IM weekly)
‐No improvement in dementia, CV outcomes
Stabler SP. Vitamin B12 deficiency. NEJM 2013;368:149‐60.
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Folate Deficiency Anemia Pearls
‐Folate deficiency also produces a macrocytic anemia, but less common than B12 due to fortified foods
‐Serum folate may be unreliable, so use methylmalonicacid (normal), homocysteine (elevated)
‐Can be seen in alcoholics, celiac disease, amyloidosis, poor nutrition, MTX, 5‐FU, TMP‐SMX
‐Exclude vitamin B12 deficiency prior to treating folatedeficiency (anemia will improve but not neuro sx)
‐Oral replacement
Anemia of Chronic Disease Pearls
‐Second most common type of anemia
‐Can produce a normochromic, normocytic anemia (early) or a microcytic anemia (late) in patients with chronic diseases (CKD, connective tissue diseases)
‐Reticulocyte count decreased
‐Ferritin inappropriately normal or elevated
‐CKD‐associated anemia responds to erythropoietin injections as long as adequate iron stores are present; goal HGB is 11‐12 g/dL
‐May see burr cells (echinocytes) on peripheral smear
Other Anemia Pearls
‐Pay attention to changes in leukocytes and platelets as this may represent a marrow issue
‐Other causes of macrocytic anemia: liver disease, hypothyroidism, myelodysplasia
‐Disorders of hemoglobin synthesis:
‐Thalassemia
‐Sickle cell trait/anemia
‐Hereditary spherocytosis
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Thrombocytopenia Pearls
Thrombocytopenia Pearls
1. Importance of peripheral smear
2. Exclude pseudothrombocytopenia
3. Exclude urgent thrombocytopenia (TTP, HIT)
4. If hemolysis is suspected (↑ LDH, bilirubin):1. COOMBS POSITIVE: Evans Syndrome (immune‐mediated)
2. COOMBS NEGATIVE: DIC Panel PostiveDIC
DIC Panel NegativeTTP
5. Nondiagnostic peripheral smear: ITP, HIT
Urgent Treatment of Thrombocytopenia
• Severe thrombocytopenia (<20,000/microliter)
• Thrombocytopenia associated with hemorrhage (mucosal, intracranial, GI, GU)
• Thrombotic thrombocytopenic purpura (TTP)
• Heparin induced thrombocytopenia (HIT)
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Thrombotic Thrombocytopenic Purpura (TTP)
• Rare (3.7 per 1,000,000)
• LIFE THREATENING
• Classic Pentad (present in <40% of patients)
1. Microangiopathic hemolytic anemia
2. Thrombocytopenia
3. Renal insufficiency
4. Fever
5. Mental status changes
TTP Pearls
• Inherited or acquired deficiency of vWFcleaving protease, leading to ↑ vWF multimers
• Spontaneous thrombi/platelet aggregation
• Associated with E. coli diarrhea, HIV, pregnancy, malignancy, drugs (ticlodipine, clopodogrel, quinine, cyclosporine)
• Check peripheral smear, PT/PTT (normal), and Coombs (negative)
TTP Peripheral Smear
TTP:Thrombocytopenia/Platelet Clumps
SchistocytesAnemia
Normal Peripheral Smear:Normal Platelet CountNormal Red Blood Cells
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TTP Pearls
• Hematologic Emergency: hospitalization, urgent consultation
• Emergent plasma exchange
• Fresh frozen plasma
• Uncertain value
– Corticosteroids
– Dipyridamole
– Aspirin
Heparin Induced Thrombocytopenia (HIT) Pearls
• Antibodies against platelet factor 4‐heparin complexes, results in platelet destruction AND activation
• Occurs days 5‐7 on heparin
• Suspect if platelets ↓ by 50%
• STOP HEPARIN (no UFH or LMWH)
• Use alternate parenteral anticoagulant (fondaparinux)
4T Scoring System for HITCATEGORY 2 POINTS 1 POINT 0 POINTS
Thrombocytopenia ↓ by >50% ↓ by 30‐50% ↓ by <30%
Timing of decrease Definitely day 5‐10 Probably day 5‐10 <4 days or no heparin exposure
Thrombosis New thrombosis Progression of existing thrombosis
None
Other causes of thrombocytopenia
None Possible Definite
SCORING:≥6: HIGH PROBABILITY4‐5: INTERMEDIATE PROBABILITY<4: LOW PROBABILITY
Lee GM, Arepally GM. Heparin‐induced thrombocytopenia. Hematology Am Soc Hematol ;2013:668‐74.
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Immune Thrombocytopenic Purpura(ITP) Pearls
• Antiplatelet antibodies against GP IIb/IIIa and Ib/IX, with ↓ platelet survival (removed in spleen)
• Only platelets are affected
– EVANS SYNDROME: ITP and hemolytic anemia (Coombs POSITIVE)
• Chronic relapsing/remitting disease
• Usually do not require treatment; role of steroids
• Chronic ITP: consider splenectomy
Thrombocytosis
Thrombocytosis Pearls
• Secondary Thrombocytosis
– Most common cause of ↑ platelets (80% of cases)
– Acute phase reactant
– Infection, malignancy, post‐splenectomy, acute hemorrhage, iron deficiency anemia, functional asplenia, RA, SLE, IBD
– Bone marrow examination if serial platelet counts do not show improvement
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Thrombocytosis Pearls
• Essential Thrombocytosis
– Hyperplasia of megakaryocytes producing large numbers of dysfunctional platelets
– Splenomegaly very common
– Normal HGB, CRP; ↑megakaryocytes in marrow
– Increased risk of AML
• Polycythemia Vera
– Elevated HGB AND platelets
– May be primary or secondary
New Oral Anticoagulants (NOAC)
XIXXIXII VII
V
IIFIBRINOGEN
FIBRIN
NOAC Review Articles
1. Hawes EM, Viera AJ. Anticoagulation. FP Essentials, Edition 422. Leawood, KS: American Academy of Family Physicians; July 2014.
2. Thachil J. The newer direct oral anticoagulants: a practical guide. Clinical Medicine 2014;14(2):165‐75.
3. Vandiver JW, Faulkner D, Erlandson M, Onysko M. Is a novel oral anticoagulant right for your patient? JFP 2014;63(1):22‐8.
4. Weitz JI, Gross PL. New oral anticoagulants: which one should my patients use? Hematology Am Soc Hematol;2012:536‐40.
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FDA‐Approved Indications for NOAC
DRUG CVA Prevention(Nonvalvular AF)
DVT/PE Treatment
DVT Prophylaxis (TKR, THR)
Dabigatran(Pradaxa)*
X X X
Apixaban(Eliquis)**
X X X
Rivaroxaban(Xarelto)**
X X
Edoxaban(Savaysa)**
X X
*Direct thrombin (Factor II) inhibitor **Factor Xa inhibitor
Contraindications/Cautions for NOACMEDICATION FDA
PREGCAT
LACTATION CAUTIONS/CONTRAINDICATIONS
Dabigatran(Pradaxa)
C NO Avoid if CrCl <15 mL/min/1.73m2, severe liver diseaseAvoid use with rifampin, carbamazepine, phenytoin, St. John’s wortCaution in the elderly, extremes of weight
Apixaban(Eliquis)
B NO Avoid if CrCl <15 mL/min/1.73m2, severe liver diseaseAvoid use with rifampin, carbamazepine, phenytoin, St. John’s wortCaution in the elderly, extremes of weight
Rivaroxaban(Xarelto)
C NO Avoid if CrCl <30 mL/min/1.73m2, severe liver diseaseAvoid use with ketoconazole, itraconazole, HIV protease inhibitors, carbamazepine, rifampin, phenytoin, St. John’s wortCaution in the elderly, extremes of weight
Hawes EM, Viera AJ. Anticoagulation. FP Essentials, Edition 422. Leawood, KS: American Academy of Family Physicians; July 2014.
Risk of Bleeding
• In general, NOAC have less intracranial bleeding than warfarin
• Increase in GI bleeding (1.5x) with rivaroxabanand dabigatran compared to warfarin
• Apixaban has the lowest rate of GI bleeding among NOAC (comparable to warfarin)
• Avoid use of other drugs that promote GI bleeding, if possible (ASA, NSAIDS)
Desai J, Granger CB, et al. Novel oral anticoagulants in gastroenterology practice. Gastrointest Endosc 2013;78:227‐39.
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What About Triple Therapy?
• Refers to the use of an oral anticoagulant with aspirin and clopidogrel (i.e. AFIB and coronary stents)
• No studies have adequately addressed the risks and benefits of triple therapy
• ACC/AHA (2014, Level C): triple therapy (ASA/clopidogrel/warfarin) probably appropriate for patients with high CHADS2 score
• No specific recommendations about NOAC and triple therapy
Asencio LA, et al. Combining antiplatelet and antithrombotic therapy (triple therapy): what are the risks and benefits? Am J Med 2014;127:579‐85.
Laboratory Monitoring of NOAC
• Not routinely indicated
• Don’t forget the renal function!
• Normal thrombin time is sensitive to exclude dabigatran
• Prothrombin time can be used to exclude rivaroxaban, apixaban
• Anti‐Xa assay in the future?
Reversal of NOAC
• No known antidote for any NOAC
• Activated charcoal for overdose (<3 hours)
• For mild to moderate bleeding, withholding medication and general supportive measures OK
• Hemodialysis can remove dabigatran
• Activated prothrombin complex (aPCC) may be used if rapid reversal needed
• ? Role of recombinant factor VIIa
• Fresh frozen plasma ineffective
Eerenberg ES, et al. Reversal of rivaroxaban and dabigatran by activated prothrombincomplex concentrate. Circulation 2011;124:1573‐9.
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Simplified Preoperative Management of Patients on NOAC
MINIMUM BLEEDING RISK: Continue NOAC or perform prior to next scheduled dose
MODERATE BLEEDING RISK: Stop NOAC 48 hours before procedure, restart 6‐8 hours postoperatively
HIGH BLEEDING RISK OR HIGH THROMBOTIC RISK: Stop NOAC 5 days before procedure and bridge with heparin, restart in 2‐3 days
Thachil J. The newer direct oral anticoagulants: a practical guide. Clinical Medicine 2014;14(2):165‐75.
Converting NOACWarfarin
CURRENT MEDICATION NEW MEDICATION RECOMMENDATION
DABIGATRAN(PRADAXA)
WARFARIN START WARFARIN 1‐3 DAYS PRIOR TO STOPPING
DABIGATRAN; CONSIDER LMWH IN HIGH RISK
PATIENTS
APIXABAN(ELIQUIS)
WARFARIN START LMWH AND WARFARIN WHEN NEXT DOSE
OF APIXABAN IS DUE
RIVAROXABAN(XARELTO)
WARFARIN START LMWH AND WARFARIN WHEN NEXT DOSE OF RIVAROXABAN IS DUE
Hawes EM, Viera AJ. Anticoagulation. FP Essentials, Edition 422. Leawood, KS: American Academy of Family Physicians; July 2014.
Converting WarfarinNOAC
CURRENT MEDICATION NEW MEDICATION RECOMMENDATION
WARFARIN DABIGATRAN(PRADAXA)
START DABIGATRAN WHEN INR <2
WARFARIN APIXABAN(ELIQUIS)
START APIXABAN WHEN INR<2
WARFARIN RIVAROXABAN(XARELTO)
START RIVAROXABAN WHEN INR <3
Hawes EM, Viera AJ. Anticoagulation. FP Essentials, Edition 422. Leawood, KS: American Academy of Family Physicians; July 2014.
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Summary
• Differentiate benign abnormalities in the CBC from life threatening changes
• Many hematological conditions require co‐management with a hematologist
• More studies and practical experience with NOACs forthcoming
Questions?
ACCP Recommendations for Length of Anticoagulation Therapy
INDICATION RECOMMENDED DURATION OF THERAPY
Symptomatic distal DVT 3 months
Proximal DVT with identifiable reversible cause/risk factor
3 months
First unprovoked proximal DVT with low bleeding risk At least 3 months, considerextended therapy
Recurrent proximal DVT At least 3 months, consider extended therapy
DVT in patient with antiphospholipid syndrome Indefinite therapy
Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e419S‐e494S.
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Warfarin Management
INR DOSE CHANGE RETEST
<1.5 Extra dose and/or increase dose by 10‐20% 1‐2 weeks
1.5‐1.9 If previously stable, continue current dose 1‐2 weeks
2.0‐3.3 Continue current dose 2‐4 weeks
3.4‐3.5 If previously stable, continue current dose 1‐2 weeks
3.6‐4.0 Decrease dose by 5‐15% 2 weeks
4.1‐5.0 Hold 1‐2 doses AND decrease dose by 15‐20% 1 week
5.1‐10.0 Hold 3 doses AND decrease dose by 15‐20%Do not use Vitamin K routinely
3 days
>10.0 Hold warfarin; Administer Vitamin K 2‐5 mgRestart warfarin when INR therapeutic with 15‐
20% reduction
1 day
Hawes EM, Viera AJ. Anticoagulation. FP Essentials, Edition 422. Leawood, KS: American Academy of Family Physicians; July 2014.
Screening for Thrombophilia
Screen for Thrombophilia
• FMHX of VTE
• VTE during pregnancy
• VTE on OCP
• Unusual location
• Unprovoked VTE
Testing Strategy
• Protein C deficiency
• Protein S deficiency
• Antithrombin III
• Factor V Leiden
• Antiphospholipid antibodies
• Prothrombin 20210A gene mutation
Middeldorp S, van Hylckama Vlieg A. Does thrombophilia testing help in the clinical management of patients? Br J Haematol 2008;143(3):321‐335.