HematologyHematologyArcher’s Online USMLE ReviewsArcher’s Online USMLE Reviews

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AnticoagulantsAnticoagulants

HeparinHeparin Low Molecular Weight HeparinLow Molecular Weight Heparin WarfarinWarfarin Direct thrombin inhibitors – Direct thrombin inhibitors –

leuperidin, argatrobanleuperidin, argatroban Factor Xa Inhibitors - fondaparinauxFactor Xa Inhibitors - fondaparinaux

HeparinsHeparinsAntithrombin 3 is a naturally occuring slow inhibitor of clotting Antithrombin 3 is a naturally occuring slow inhibitor of clotting

pathway. Heparin binds to AT-3 and converts it from slow to pathway. Heparin binds to AT-3 and converts it from slow to rapid inhibitor by forming a ternary complex with AT-3 and rapid inhibitor by forming a ternary complex with AT-3 and thrombinthrombin

Unfractionated Heparin : Unfractionated Heparin : Unfractionated heparinUnfractionated heparin is a is a heterogeneous mixture of polysaccharide chains with a heterogeneous mixture of polysaccharide chains with a mean molecular weight of 15,000 Daltons. Given I.V. mean molecular weight of 15,000 Daltons. Given I.V. Requires Inpatient Rx. Higher incidence of Throbocytopenia Requires Inpatient Rx. Higher incidence of Throbocytopenia and osteopenia. Monitored by measuring APTTand osteopenia. Monitored by measuring APTT

LMWH: Derived from heparin. Molecular weight-5000 D. LMWH: Derived from heparin. Molecular weight-5000 D. Can be given twice daily doses on OP basis. Less incidence Can be given twice daily doses on OP basis. Less incidence of throbocytopenia and osteopenia. LMWHs have more anti of throbocytopenia and osteopenia. LMWHs have more anti factor X a activity than UF heparin. LMWH activity is factor X a activity than UF heparin. LMWH activity is monitored by factor Xa activity.monitored by factor Xa activity.

Heparins can cause HyperkalemiaHeparins can cause Hyperkalemia

Heparin Induced Skin Necrosis Affects middle age women with history of thrombotic

disease Characterized by the formation of one or more painful red

plaques or necrotic skin lesions. 5 days or more after starting heparin treatment. Earlier in

those treated previously with heparin. Some patients develop thrombocytopenia when lesion first

appears, often with paradoxical thrombosis.(HIT) Is not always associated with thrombocytopenia

A rare complication of heparin characterized by immune complex formation and thrombosis.

HIT Should be suspected if the patient develop skin necrosis in areas of SQ injection or IV site.

Rx – stop Heparin + start Direct thrombin inhibitors or heparinoids ( Leupiridin or Argatroban ) ( i.e; treat like HIT)

WarfarinWarfarin Mechanism of actionMechanism of action

AntagonistAntagonistSkin necrosisSkin necrosis

UsesUsesINR monitoringINR monitoring

Dealing with Supratherapeutic INR on case by case Dealing with Supratherapeutic INR on case by case basisbasis

Dealing with Sub therapeutic INR ( APLA, OBESITY, Dealing with Sub therapeutic INR ( APLA, OBESITY, WARFARIN RESISTANCE, INTERACTIONS, NON-WARFARIN RESISTANCE, INTERACTIONS, NON-

COMPLIANCE) COMPLIANCE)

WARFARIN: MECHANISM OF ACTIONWARFARIN: MECHANISM OF ACTION

Inactive factors II, VII, IX, and X

Proteins S and C

Active factors II, VII, IX, and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K, which is essential for Prevents the reduction of vitamin K, which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

PLASMA HALF-LIVES OF VITAMIN K-PLASMA HALF-LIVES OF VITAMIN K-DEPENDENT PROTEINSDEPENDENT PROTEINS

Factor IIFactor II 72h72h

Factor VIIFactor VII 6h6h

Factor IXFactor IX 24h24h

Factor XFactor X 36h36h

Peak anticoagulant effect may be delayed by 72 to 96 hoursPeak anticoagulant effect may be delayed by 72 to 96 hours

PROTEIN S HALF LIFE : shorter than abovePROTEIN S HALF LIFE : shorter than above

Coumadin Skin NecrosisCoumadin Skin Necrosis• Warfarin Procoagulant Effect in Warfarin Procoagulant Effect in

first few hours can cause first few hours can cause warfarin skin necrosis due to warfarin skin necrosis due to thrombosis.thrombosis.

• Concomitant heparin use can Concomitant heparin use can decrease the incidencedecrease the incidence

• Patients developing coumadin Patients developing coumadin skin necrosis should be skin necrosis should be evaluated for Protein C evaluated for Protein C deficiencydeficiency

Rx Rx

Stop CoumadinStop Coumadin Use heparin until the necrotic lesions Use heparin until the necrotic lesions

heal.heal.

Correcting Supra-Correcting Supra-Therapeutic INRTherapeutic INR

Approach!Approach!

Warfarin has a narrow therapeutic indexWarfarin has a narrow therapeutic index Therapeutic INR typically targeted at 2-3. Therapeutic INR typically targeted at 2-3. The risk of bleeding increases significantly when the INR > The risk of bleeding increases significantly when the INR >

4-6. However, the absolute risk is still low at 5.5 bleeding 4-6. However, the absolute risk is still low at 5.5 bleeding events per 1000 per day events per 1000 per day

Therefore, patients with an INR < 9 and no significant Therefore, patients with an INR < 9 and no significant bleeding bleeding Manage by omitting subsequent doses of Manage by omitting subsequent doses of warfarin, more frequent monitoring of the INR, and warfarin, more frequent monitoring of the INR, and resumption of therapy at a lower dose when the INR is resumption of therapy at a lower dose when the INR is therapeutic. therapeutic.

When rapid reversal of the INR is needed, fresh frozen When rapid reversal of the INR is needed, fresh frozen plasma, prothrombin complex, or recombinant factor VIIa plasma, prothrombin complex, or recombinant factor VIIa can be administered. can be administered.

Administration of coagulation factors provides only a Administration of coagulation factors provides only a temporary solution due to the short half-life of the provided temporary solution due to the short half-life of the provided clotting factors (3-4 hours for Factor VII), compared with a clotting factors (3-4 hours for Factor VII), compared with a duration of action of 2 to 5 days for warfarin, as well as duration of action of 2 to 5 days for warfarin, as well as relative instability of clotting factors upon administration.relative instability of clotting factors upon administration.

Administration of either fresh frozen plasma or factor Administration of either fresh frozen plasma or factor concentrates will decrease the PT/INR for 4 to 6 hours concentrates will decrease the PT/INR for 4 to 6 hours So, So, complete return to a therapeutic INR will require complete return to a therapeutic INR will require supplementation with vitamin Ksupplementation with vitamin K

Rxng Supratherapeutic INRRxng Supratherapeutic INR

Treatment of a supra therapeutic INR requires a Treatment of a supra therapeutic INR requires a balance between reducing the risk for hemorrhage balance between reducing the risk for hemorrhage while minimizing the risk of thrombembolism. while minimizing the risk of thrombembolism.

Treatment approaches are based on the current Treatment approaches are based on the current INR, presence of bleeding, and the time frame in INR, presence of bleeding, and the time frame in which reversal is required.which reversal is required.

Vitamin K1 CAN BE GIVEN to reverse the Vitamin K1 CAN BE GIVEN to reverse the anticoagulation effect of warfarin. anticoagulation effect of warfarin.

The The most appropriate dose of vitamin K1most appropriate dose of vitamin K1 is is the one that lowers the INR to a safe level without the one that lowers the INR to a safe level without resulting in a subtherapeutic INR. resulting in a subtherapeutic INR.

High doses of vitamin K1 are effective but may High doses of vitamin K1 are effective but may lead to warfarin resistance for a week or more, lead to warfarin resistance for a week or more, resulting in an increased risk for resulting in an increased risk for thromboembolism. In such cases, heparin should thromboembolism. In such cases, heparin should be given until the effects of the vitamin K1 are be given until the effects of the vitamin K1 are complete. ( complete. ( note this pointnote this point) )

Forms of Vitamin KForms of Vitamin K Available in subcutaneous, IV and oral formsAvailable in subcutaneous, IV and oral forms Subcutaneous route Subcutaneous route delayed onset and is less delayed onset and is less

predictable.predictable. If rapid reversal is desired, the IV route should be utilized, If rapid reversal is desired, the IV route should be utilized,

as this route has the fastest onset of action. ( as this route has the fastest onset of action. ( Historically, intravenous vitamin K1 has been associated with an increased risk of anaphylaxis. A retrospective review of anaphylactic reactions associated with IV vitamin K1 from the Mayo Clinic revealed that the risk of anaphylaxis with vitamin K1 was 3 per 10,000 doses—a rate comparable to all forms of penicillin and less than that of IV iron dextran. If is administered by the IV route, lower doses and slower infusion rates are recommended))

Unless rapid reversal of the INR is critical, oral vitamin K1 is Unless rapid reversal of the INR is critical, oral vitamin K1 is the preferred route of administration. the preferred route of administration.

In the United States, oral vitamin K1 is only available as a 5 In the United States, oral vitamin K1 is only available as a 5 mg tablet (Mephyton®). Therefore, oral doses prescribed mg tablet (Mephyton®). Therefore, oral doses prescribed should reflect even divisions of 5 mg (e.g., 2.5 mg).should reflect even divisions of 5 mg (e.g., 2.5 mg).

Forms of Vitamin K

Route Advantages Disadvantages

IV •Fastest Onset of Action

•Must be given by slow IV infusion •Warfarin resistance

Subcutaneous •Lower risk of anaphylaxis

•Delayed onset •Unpredictable response •Least desired route

Oral •Safest route •Low risk of anaphylaxis •No IV site needed

•Slower onset of action •Warfarin resistance

Management of Elevated INR in Patients Receiving Vitamin K Antagonists

INR Bleeding Present Rapid Reduction Required Management*

< 5 No No Lower dose by 10% or omit dose; resume at lower dose when INR is therapeutic i.e; 2 TO 3

5-9 No No Omit one or two doses, resume at lower dose by 10%.

No Yes — high risk May give vitamin K 2.5 mg orally if at increased risk for bleeding.

No Yes—surgery 2-4 mg oral vitamin K1 for

reduction of INR in 24 hours; if INR still high, can repeat with 1-2 mg orally.

≥9 No No Hold dose and give vitamin K1 10 mg orally to

reduce INR in 24 hours; may repeat vitamin K1as

necessary. Resume at lower dose when therapeutic.

Any Yes—Serious Bleeding Yes Hold dose, give vitamin K1

10 mg by slow IV infusion, along with fresh frozen plasma, prothrombin complex, or recombinant factor VIIa; vitamin K1 may

be repeated every 12 hours.

Any Yes—Life Threatening Yes Hold dose, give prothrombin complex along with vitamin K1 10

mg by slow IV infusion; repeat if necessary depending on INR.

When the INR is elevated in a patient who When the INR is elevated in a patient who has been on a consistent dose of warfarin has been on a consistent dose of warfarin for past few weeks for past few weeks Always, consider Always, consider why it is elevatedwhy it is elevated

Antibiotics can potentate by causing Antibiotics can potentate by causing Vitamin k deficiency.Vitamin k deficiency.

If drug interaction is considered If drug interaction is considered stop stop the other drug if possible. If stopping the the other drug if possible. If stopping the interacting drug is feasible and if INR < 5, interacting drug is feasible and if INR < 5, no need to reduce the warfarin doseno need to reduce the warfarin dose

Addressing Sub Addressing Sub Therapeutic INRTherapeutic INR

Approach on increasing the Approach on increasing the dosedose

Warfarin ResistanceWarfarin Resistance

Sub-Therapeutic INR Sub-Therapeutic INR INR< 1.5 – Increase the dose by 10 to INR< 1.5 – Increase the dose by 10 to

20%, consider extra dose and repeat 20%, consider extra dose and repeat INR in 4 to 8 days. INR in 4 to 8 days.

1.5 to 2.4 – Increase dose by 5 to 1.5 to 2.4 – Increase dose by 5 to 10%. Repeat INR in one to two weeks10%. Repeat INR in one to two weeks

2.5 to 3.5 – No change in dose. 2.5 to 3.5 – No change in dose. Repeat INR is the # of consecutive in-Repeat INR is the # of consecutive in-range INRs (For example, if a patient range INRs (For example, if a patient has had three consecutive in-range has had three consecutive in-range INR values, recheck in 3 weeks. INR values, recheck in 3 weeks. Maximum repeatable period not Maximum repeatable period not longer than 4 weekslonger than 4 weeks ) )

Foods that can cause Foods that can cause sub-therapeutic INRsub-therapeutic INR

Foods with very high vitamin K content Foods with very high vitamin K content (more than 200 mcg) — Brussel sprouts, (more than 200 mcg) — Brussel sprouts, chickpeas, collard greens, coriander, chickpeas, collard greens, coriander, endive, kale, liver, parsley, red leaf endive, kale, liver, parsley, red leaf lettuce, spinach, Swiss chard, black or lettuce, spinach, Swiss chard, black or green teas, turnip greens, watercress.green teas, turnip greens, watercress.

    Foods with high vitamin K content (100-    Foods with high vitamin K content (100-200 mcg) include basil, broccoli, 200 mcg) include basil, broccoli, butterhead lettuce, canola oil, chives, butterhead lettuce, canola oil, chives, coleslaw, cucumbers (with peel), green coleslaw, cucumbers (with peel), green onions, mustard greens, soybean oil.onions, mustard greens, soybean oil.

ScenariosScenarios

DVTDVT Pulmonary EmbolismPulmonary Embolism DVT prophylaxisDVT prophylaxis Atrial fibrillationAtrial fibrillation Prosthetic ValvesProsthetic Valves Mural thrombusMural thrombus Acute Coronary SyndromeAcute Coronary Syndrome

Deep Vein ThrombosisDeep Vein Thrombosis

Pulmonary EmbolismPulmonary Embolism

AbnormalBlood Flow

AbnormalVessel Wall

Dr. Rudolph Virchow1821-1902

The Hypercoagulable State

AbnormalBlood

Deep Vein ThrombosisDeep Vein Thrombosis

Clinical associationsClinical associations

ImmobilityImmobilityObesityObesitySmokingSmokingCancerCancerPregnancyPregnancyEstrogen therapyEstrogen therapy

Economy class syndromeEconomy class syndrome

Economy-class syndrome is a name used Economy-class syndrome is a name used by the media to describe by the media to describe Venous Venous Thrombo-EmbolismThrombo-Embolism that can occur in that can occur in anyone - but has been of particular worry anyone - but has been of particular worry in air travellers.in air travellers.

Incidence of DVT & PE increases with the Incidence of DVT & PE increases with the flight distanceflight distance

Prevention tips : Drink fluids, avoid Prevention tips : Drink fluids, avoid caffeine and alcohol, keep moving legs caffeine and alcohol, keep moving legs and wear graduated support stockings and wear graduated support stockings designed for travel.designed for travel.

Proximal

Distal

Proximal vs. Distal DVTProximal vs. Distal DVT Thrombosis confined to deep calf veins is Distal Thrombosis confined to deep calf veins is Distal

DVT where as thrombosis at or above popliteal DVT where as thrombosis at or above popliteal veins is Proximal DVT.veins is Proximal DVT.

A distal DVT becomes clinically important when it A distal DVT becomes clinically important when it extends proximallyextends proximally

Risk of PE is much higher with proximal DVT. Risk of PE is much higher with proximal DVT. Silent PE occurs in about 50% of pts with proximal Silent PE occurs in about 50% of pts with proximal DVT.DVT.

All patients with Proximal DVT are at increased All patients with Proximal DVT are at increased long term risk for chronic venous insufficiency.long term risk for chronic venous insufficiency.

Compression ultrasound is more sensitive to Compression ultrasound is more sensitive to proximal DVT when compared to distal DVT.proximal DVT when compared to distal DVT.

Idiopathic DVTIdiopathic DVT

A case of DVT where no evidence of A case of DVT where no evidence of underlying obvious cause such as underlying obvious cause such as surgery, trauma or known surgery, trauma or known malignancy is present.malignancy is present.

Search for a hypercoagulable state in Search for a hypercoagulable state in such conditionssuch conditions

Hypercoagulable states : inherited or Hypercoagulable states : inherited or acquiredacquired

Evaluating Idiopathic Evaluating Idiopathic Venous Venous

ThromboembolismThromboembolism

APPROACH

Hypercoagulabilty – Whom to test?Hypercoagulabilty – Whom to test?

DVT occurring in a pt < 50 yrs of ageDVT occurring in a pt < 50 yrs of age Positive Family Hx of Venous Positive Family Hx of Venous

thromboembolismthromboembolism Recurrent episodes of unexplained Venous Recurrent episodes of unexplained Venous

thromboembolismthromboembolism Don’t forget to include Homocysteine - Don’t forget to include Homocysteine -

When homocysteine levels are elevated in When homocysteine levels are elevated in the presence of factor V Leiden or the the presence of factor V Leiden or the prothrombin gene G20210A mutation, risk prothrombin gene G20210A mutation, risk of recurrent thrombosis appears to be of recurrent thrombosis appears to be increased beyond the risk associated with increased beyond the risk associated with any one defect alone any one defect alone

Hypercoagulabilty – When to test?Hypercoagulabilty – When to test?

HeparinHeparin• Controversial AT-III (heparin vs acute event)Controversial AT-III (heparin vs acute event)• Most coagulation based test for APLA Most coagulation based test for APLA

Hexagonal phospholipid not affectedHexagonal phospholipid not affected

WarfarinWarfarin• Protein C and protein SProtein C and protein S• Need to wait 3 weeks before testing protein SNeed to wait 3 weeks before testing protein S• Most coagulation based APLA testsMost coagulation based APLA tests

Hypercoagulable statesHypercoagulable states

InheritedInherited

-“ The big five”-“ The big five”• Factor V LeidenFactor V Leiden• Prothrombin gene mutationProthrombin gene mutation• Protein S deficiencyProtein S deficiency• Protein C deficiencyProtein C deficiency• Antithrombin III deficiency Antithrombin III deficiency

Factor V LeidenFactor V Leiden

Most common inherited risk factorMost common inherited risk factor Often associated with other risk Often associated with other risk

factors e.g: homocysteinefactors e.g: homocysteine Dramatic increase in risk with Dramatic increase in risk with

estrogens ( OC Pills)estrogens ( OC Pills)

Hypercoagulability statesHypercoagulability states

AcquiredAcquired CancerCancer Antiphospholipid antibody syndromeAntiphospholipid antibody syndrome Nephrotic syndromeNephrotic syndrome Inflammatory bowel disease. Etiology: Inflammatory bowel disease. Etiology:

inflammatory cytokines, low protein sinflammatory cytokines, low protein s HomocysteineHomocysteineClues to Acquired state : older age at the Clues to Acquired state : older age at the

time of onset, refractory to Warfarin , both time of onset, refractory to Warfarin , both venous and arterial thromboembolism.venous and arterial thromboembolism.

DVT and CancerDVT and Cancer

Clues Clues – –

Bilateral DVTs, Arterial and venous Bilateral DVTs, Arterial and venous thrombosis and Warfarin refractory thrombosis and Warfarin refractory thrombosisthrombosis

DVT DiagnosisDVT Diagnosis

Differential DiagnosisDifferential Diagnosis

CellulitisCellulitis Knee pathology i.e. ruptured Knee pathology i.e. ruptured

synovial cystsynovial cyst Calf muscle strainCalf muscle strain Calf muscle hematomaCalf muscle hematoma

INVESTIGATIONSINVESTIGATIONS Venogram : Gold standard. Rarely performed due Venogram : Gold standard. Rarely performed due

to accuracy of non invasive testing. Risks: to accuracy of non invasive testing. Risks: phlebitis, hypersensitivity, nephrotoxicity, phlebitis, hypersensitivity, nephrotoxicity, cardiotoxicitycardiotoxicity

Venous duplex ultrasound : non invasive, Venous duplex ultrasound : non invasive, accurate, first line study in moderate to high risk accurate, first line study in moderate to high risk DVT. Specificity : 95%. Sensitivity 97% for DVT. Specificity : 95%. Sensitivity 97% for proximal DVT and only 73% for distal DVT. Can proximal DVT and only 73% for distal DVT. Can identify other pathology e.g.: calf haematoma, identify other pathology e.g.: calf haematoma, bakers cyst, abscessesbakers cyst, abscesses

MRI : 90% sensitive and specific for acute MRI : 90% sensitive and specific for acute Proximal DVT.Proximal DVT.

D-Dimer assaysD-Dimer assays D-Dimer should not be used as a screening test. D-Dimer should not be used as a screening test.

Can be used as a first line test in pts with low Can be used as a first line test in pts with low pretest probability for DVT. pretest probability for DVT.

The utility of D-Dimer is mainly to reduce the The utility of D-Dimer is mainly to reduce the number of ultrasound testings.number of ultrasound testings.

The negative predictive value of a d-dimer assay The negative predictive value of a d-dimer assay falls as the pretest probability for DVT increases. falls as the pretest probability for DVT increases. An assay with a sensitivity of 80% has a negative An assay with a sensitivity of 80% has a negative predictive value (NPV) of predictive value (NPV) of 97.6% in a low-risk 97.6% in a low-risk patientpatient. However, the NPV of the same assay . However, the NPV of the same assay is is only 33%only 33% in high-risk patientsin high-risk patients with a pretest with a pretest probability of 90% for DVT. probability of 90% for DVT.

CLINICAL ( PRETEST) PROBABILITY OF CLINICAL ( PRETEST) PROBABILITY OF DVTDVT

WELLS DVT SCORE SYSTEM ( most popular )WELLS DVT SCORE SYSTEM ( most popular ) Clinical Parameter Clinical Parameter

ScoreScore

Active cancer (treatment ongoing, or within + 1 6 months or palliative) Paralysis or recent plaster immobilization + 1 of the lower extremities Recently bedridden for >3 d or major + 1 surgery <4 wk Localized tenderness along the distribution + 1 of the deep venous system Entire leg swelling + 1 Calf swelling >3 cm compared to the asympto + 1 - matic leg Pitting edema (greater in the symptomatic leg) + 1 Previous DVT documented + 1 Collateral superficial veins (non varicose) + 1 Alternative diagnosis (as likely or > that of DVT ) - 2

Wells DVT Clinical Score ( contd )Wells DVT Clinical Score ( contd )

Score of Zero – low probability ( 0 to 13%)

Score 1 – 2 - moderate probability ( 13 to 30% probability)

Score > or = 3 - high probability ( 49 to 81%probability)

Complications - DVTComplications - DVT

Pulmonary EmbolismPulmonary Embolism Post obstructive syndrome : pain and Post obstructive syndrome : pain and

edema in the affected limb without edema in the affected limb without new clot formationnew clot formation

Chronic venous insufficiency Chronic venous insufficiency Rarely, Rarely, thrombosisthrombosis is massive, is massive,

causing vascular compromise of the causing vascular compromise of the leg due to high venous pressure (i.e., leg due to high venous pressure (i.e., phlegmasia cerulea dolens).phlegmasia cerulea dolens).

DEEP VEIN DEEP VEIN THROMBOSISTHROMBOSIS

TREATMENTTREATMENT

TreatmentTreatment

Anticoagulation – heparin, warfarin, Anticoagulation – heparin, warfarin, lmwh – overlapping treatmentslmwh – overlapping treatments

IVC filters – greenfield filterIVC filters – greenfield filter

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Dosage to be individualized according to patient’s Dosage to be individualized according to patient’s INR response. Target INR -2-3INR response. Target INR -2-3Use of large loading dose may lead to Use of large loading dose may lead to hemorrhage and other complications.hemorrhage and other complications.

Initial dose: 2-5 mg once dailyInitial dose: 2-5 mg once daily Maintenance dose: 2-10 mg once dailyMaintenance dose: 2-10 mg once daily Start heparin on day 1 and warfarin in the Start heparin on day 1 and warfarin in the

evening of Day1 or on Day2. Heparin is usually evening of Day1 or on Day2. Heparin is usually discontinued after 4-5 days. discontinued after 4-5 days. Before discontinuing, Before discontinuing, ensure INR is in therapeutic range for 2 consecutive ensure INR is in therapeutic range for 2 consecutive daysdays

Monitor daily until INR is in therapeutic range, Monitor daily until INR is in therapeutic range, then 3 times weekly for 1-2 weeks, then less then 3 times weekly for 1-2 weeks, then less often (every 4 to 6 weeks) often (every 4 to 6 weeks)

CONTARINDICATIONS AND CONTARINDICATIONS AND PRECAUTIONS - WARFARINPRECAUTIONS - WARFARIN

Hypersensitivity to warfarinHypersensitivity to warfarin Condition with risk of hemorrhageCondition with risk of hemorrhage Hemorrhagic tendencyHemorrhagic tendency Protein C & S deficiencyProtein C & S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Microembolization Microembolization Teratogenecity : contraindicated Teratogenecity : contraindicated

in pregnancyin pregnancy Agranulocytosis, leukopenia, Agranulocytosis, leukopenia,

diarrhea,diarrhea,

nausea, anorexia.nausea, anorexia.

Uncomplicated DVT - OP managementUncomplicated DVT - OP management Any reason for Hospitalization ?Any reason for Hospitalization ?

potential probm with home Rxpotential probm with home Rx No probm with Home RxNo probm with Home Rx

Hospitalize Give 1st dose S.C LMWH StatHospitalize Give 1st dose S.C LMWH StatGive BID S.C LMWH + Warfarin Begin Warfarin in Doses 5mg QDGive BID S.C LMWH + Warfarin Begin Warfarin in Doses 5mg QDOngoing Evaluation Assign a visiting nurse for twice Ongoing Evaluation Assign a visiting nurse for twice daily injs ( until the pt or family daily injs ( until the pt or family member can inject ) Daily PT and member can inject ) Daily PT and CBC with platelet count. CBC with platelet count. After atleast 5 days twice daily After atleast 5 days twice daily injs of LMWH, a therapeutic INR injs of LMWH, a therapeutic INR for 2 consecutive days – d/c LMWH for 2 consecutive days – d/c LMWH and follow warfarin carefully as per and follow warfarin carefully as per routine for DVT. routine for DVT. Repeat physician evaluation by 5-7, Repeat physician evaluation by 5-7, if no problem, repeat 1 wk later and if no problem, repeat 1 wk later and as per routine for DVT. as per routine for DVT.

Reasons for hospitalization in DVTReasons for hospitalization in DVT

Signs and symptoms of PESigns and symptoms of PE Co-existing medical illness – anemia, lung Co-existing medical illness – anemia, lung

disease, previous bleeding, high risk of disease, previous bleeding, high risk of bleeding or clottingbleeding or clotting

Depression or any other mental illness Depression or any other mental illness that restricts pt’s co-operation and that restricts pt’s co-operation and compliance with the home Rx.compliance with the home Rx.

Insurance problem or other logistic Insurance problem or other logistic difficulty that limits pt’s access to home difficulty that limits pt’s access to home Rx, nursing care, monitoring, food & Rx, nursing care, monitoring, food & sheltershelter

Duration of therapyDuration of therapy

??

Duration depends on risk factor for Duration depends on risk factor for DVTDVT

Risk of recurrence depends on type of risk factor. Risk of recurrence depends on type of risk factor. If 1If 1stst DVT occurred after a major risk factor, DVT occurred after a major risk factor, recurrence is 3% where as if it occurred after recurrence is 3% where as if it occurred after minor risk factor recurrence is 10% minor risk factor recurrence is 10% So, stratify So, stratify pts based on risk factor and then decide durationpts based on risk factor and then decide duration

Major transient risk factors : Major surgery, major Major transient risk factors : Major surgery, major medical illness and leg casting.medical illness and leg casting.

Minor transient risk factors : OC Pills, HRTMinor transient risk factors : OC Pills, HRT High risk thrombophilias : Homzygos Prothrombin High risk thrombophilias : Homzygos Prothrombin

gene mutation, Homozygos Factor v leiden, gene mutation, Homozygos Factor v leiden, antithrombin, protein c and protein s deficiencies antithrombin, protein c and protein s deficiencies and APLA Syndromeand APLA Syndrome

Low risk thrombophilias : Heterozygosity for Low risk thrombophilias : Heterozygosity for prothrobin gene mutation and Factor V leidenprothrobin gene mutation and Factor V leiden

Recommendations – Duration of Anticoagulant Rx in pts with DVTRecommendations – Duration of Anticoagulant Rx in pts with DVTPatient Patient characteristicscharacteristics

Risk of recurrence Risk of recurrence (%)(%)

- In the year after - In the year after discontinuationdiscontinuation

Duration of TherapyDuration of Therapy

a.a.Major transient risk Major transient risk factor factor

b.b.Minor risk factor, no Minor risk factor, no thrombophilia thrombophilia

c.c.Idiopathic event, no Idiopathic event, no or low risk or low risk thrombophiliathrombophilia

d.d.Idiopathic event, Idiopathic event, high risk high risk thrombophiliathrombophilia

e.e.More than one More than one idiopathic eventidiopathic event

f.f.Cancer, other Cancer, other ongoing risk factorongoing risk factor

Ref: NEJM, 2004, 351Ref: NEJM, 2004, 351

3%3%

<10% if risk factor <10% if risk factor avoided. >10% if avoided. >10% if persistentpersistent

<10%<10%

>10%>10%

>10%>10%

>10%>10%

3 months3 months

6 months6 months

Until factor resolvesUntil factor resolves

6 months6 months

IndefiniteIndefinite

IndefiniteIndefinite

Indefinite. Consider Indefinite. Consider long term Rx with long term Rx with LMWH in pts with LMWH in pts with cancercancer

Contraindications - Anticoagulant Contraindications - Anticoagulant RXRX

Absolute contraindications:Absolute contraindications: Active bleedingActive bleeding Severe bleeding diatheses or platelet count< 20,000/mm3Severe bleeding diatheses or platelet count< 20,000/mm3 Neurosurgery, ocular surgery or intracranial bleeding in Neurosurgery, ocular surgery or intracranial bleeding in

past 10 dayspast 10 days

Relative contraindications:Relative contraindications: Mild/moderate bleeding diatheses or thrombocytopeniaMild/moderate bleeding diatheses or thrombocytopenia Recent major traumaRecent major trauma Major abdominal surgery in past 2 daysMajor abdominal surgery in past 2 days Brain metastasesBrain metastases Gastro/genitourinary bleeding in past 2wksGastro/genitourinary bleeding in past 2wks EndocarditisEndocarditis Severe hypertension at presentation ( SBP>200 and Severe hypertension at presentation ( SBP>200 and

DBP>120)DBP>120)

Case Study Case Study A 79-year-old man is admitted to the medical ward 3 days status A 79-year-old man is admitted to the medical ward 3 days status

post subdural hematoma drainage, C3 cervical spine fracture, and post subdural hematoma drainage, C3 cervical spine fracture, and fixation of multiple extremity fractures sustained in a motor fixation of multiple extremity fractures sustained in a motor vehicle accident. The patient is now awake and oriented to person, vehicle accident. The patient is now awake and oriented to person, place, and time, but is a lower cervical spine incomplete place, and time, but is a lower cervical spine incomplete quadriplegic. Physical examination reveals some minimal quadriplegic. Physical examination reveals some minimal sensation in the legs, but no ability to move the extremities. There sensation in the legs, but no ability to move the extremities. There is a Foley catheter in place that is draining yellow colored urine. is a Foley catheter in place that is draining yellow colored urine. Doppler ultrasonography demonstrates a thrombus in the left Doppler ultrasonography demonstrates a thrombus in the left popliteal vein. The most important next step in the management popliteal vein. The most important next step in the management of this patient isof this patient is

A. daily Doppler ultrasonography of the lower extremitiesA. daily Doppler ultrasonography of the lower extremities B. inferior vena cava filter placementB. inferior vena cava filter placement C. subcutaneous heparinC. subcutaneous heparin D. tissue plasminogen activator thrombolysisD. tissue plasminogen activator thrombolysis E. warfarinE. warfarin F. weekly ventilation/perfusion scans for a pulmonary embolusF. weekly ventilation/perfusion scans for a pulmonary embolus

Case StudyCase Study A 49-year-old man comes to clinic for follow up and monitoring of A 49-year-old man comes to clinic for follow up and monitoring of

his oral anticoagulation levels. The patient is postoperative day 62 his oral anticoagulation levels. The patient is postoperative day 62 from a left total knee replacement. On postoperative day number from a left total knee replacement. On postoperative day number 2 he suffered a 2 he suffered a pulmonary embolismpulmonary embolism. He was placed on . He was placed on intravenous unfractionated heparin and then oral warfarin. He was intravenous unfractionated heparin and then oral warfarin. He was discharged home with follow-up instructions to return to the clinic discharged home with follow-up instructions to return to the clinic for monitoring of his prothrombin time/international normalized for monitoring of his prothrombin time/international normalized ratio (INR) every 3 weeks. On return to the clinic today his PT/INR ratio (INR) every 3 weeks. On return to the clinic today his PT/INR is found to be 22.4/7.3. His physical examination is unremarkable. is found to be 22.4/7.3. His physical examination is unremarkable. The most appropriate management at this time is toThe most appropriate management at this time is to

A. admit the patient to the hospitalA. admit the patient to the hospital B. instruct the patient to discontinue warfarin and return in 1 B. instruct the patient to discontinue warfarin and return in 1

weekweek C. instruct the patient to discontinue warfarin week until his next C. instruct the patient to discontinue warfarin week until his next

visit in 3 weeksvisit in 3 weeks D. give protamine sulfate, intravenouslyD. give protamine sulfate, intravenously E. give vitamin K and follow up with the patient at his next visitE. give vitamin K and follow up with the patient at his next visit

Thrombosis in Thrombosis in PregnancyPregnancy

Preventing Thrombosis in Preventing Thrombosis in PregnancyPregnancy

Give prophylaxis with heparin during pregnancy and Give prophylaxis with heparin during pregnancy and continued heparin or warfarin for 6 weeks continued heparin or warfarin for 6 weeks postpartum in women with high risk of recurrent postpartum in women with high risk of recurrent thrombosis: thrombosis:

Recent thromboembolism (within the previous 6 Recent thromboembolism (within the previous 6 months) months)

An indication for lifelong anticoagulation An indication for lifelong anticoagulation Previous thrombosis with a thrombophilia Previous thrombosis with a thrombophilia

associated with a high risk of recurrent associated with a high risk of recurrent thrombosis (homozygotes for factor V Leiden, thrombosis (homozygotes for factor V Leiden, homozygotes for the prothrombin gene mutation, homozygotes for the prothrombin gene mutation, or antiphospholipid antibodies or antiphospholipid antibodies

A history of recurrent thromboembolism A history of recurrent thromboembolism

Consider heparin prophylaxis antepartum Consider heparin prophylaxis antepartum and intrapartum, and heparin or warfarin and intrapartum, and heparin or warfarin prophylaxis postpartum in women with prophylaxis postpartum in women with one previous thromboembolic event even one previous thromboembolic event even without without underlying thrombophilia, family underlying thrombophilia, family history, or other risk factors (such as history, or other risk factors (such as obesity, smoking, recent surgery, obesity, smoking, recent surgery, immobilization, advanced age, and parity). immobilization, advanced age, and parity).

Advise pregnant women, especially those Advise pregnant women, especially those with a history of thrombosis or with a history of thrombosis or thrombophilia, to stop smoking thrombophilia, to stop smoking

Rxng Thrombo-embolism in Rxng Thrombo-embolism in PregnancyPregnancy

Avoid the use of warfarin during Avoid the use of warfarin during pregnancy because it crosses the placenta pregnancy because it crosses the placenta and is associated with teratogenesis and and is associated with teratogenesis and increased fetal morbidity and mortality.increased fetal morbidity and mortality.

Treat with LMWH @ therapeutic doses. Treat with LMWH @ therapeutic doses. Continue long-term prophylaxis against Continue long-term prophylaxis against recurrent venous thromboembolism after recurrent venous thromboembolism after the postpartum period and completion of the postpartum period and completion of therapy using warfarintherapy using warfarin, aiming for a target , aiming for a target INR of 2 to 3 ( usually 6 mos if no other hx INR of 2 to 3 ( usually 6 mos if no other hx of thrombophilia is present)of thrombophilia is present)

AnemiasAnemias

AnemiasAnemias Look At MCV Look At MCV Microcytic, Macrocytic & Normocytic Microcytic, Macrocytic & Normocytic Iron deficiency – Colon ca scenarios, Fibroids, malabsorption Iron deficiency – Colon ca scenarios, Fibroids, malabsorption

syndromes (Celiac sprue), Gastric bypass surgery (Iron is syndromes (Celiac sprue), Gastric bypass surgery (Iron is mainly absorbed in the duodenum and jejunum)mainly absorbed in the duodenum and jejunum)

B12, Folic acid deficiencyB12, Folic acid deficiency B12 deficiency in the elderlyB12 deficiency in the elderly Sideroblastic AnemiaSideroblastic Anemia ThalassemiasThalassemias Autoimmune Hemolytic Anemias – initial rx sterods, then Autoimmune Hemolytic Anemias – initial rx sterods, then

IVIG, if unresponsive splenectomyIVIG, if unresponsive splenectomy Hereditary SpherocytosisHereditary Spherocytosis G6PD Deficiency – sulfa, dapsone, primaquineG6PD Deficiency – sulfa, dapsone, primaquine Sickle Cell Anemia – Crisis, Aplastic crisis, Acute chest Sickle Cell Anemia – Crisis, Aplastic crisis, Acute chest

syndrome, Avascular necrosis, osteomyelitis, syndrome, Avascular necrosis, osteomyelitis, autospenectomy, Folate supplement importanceautospenectomy, Folate supplement importance

Aplastic Anemia Aplastic Anemia Anemia of Renal Disease – Give EPO if Hgb < 10 and Anemia of Renal Disease – Give EPO if Hgb < 10 and

supplement iron if Tsat < 20%supplement iron if Tsat < 20% Anemia of Chronic DiseaseAnemia of Chronic Disease Bone marrow biopsy – indications in AnemiaBone marrow biopsy – indications in Anemia

Microcytic AnemiasMicrocytic Anemias

Importance of RDWImportance of RDW Peripheral smear – increase in Peripheral smear – increase in

central pallorcentral pallor Iron studies – IRON/TIBC, FerritinIron studies – IRON/TIBC, Ferritin Differentiate from AOCD – in AOCD, Differentiate from AOCD – in AOCD,

ferritin normal/ high, iron low, tibc ferritin normal/ high, iron low, tibc low low

Rx – Iron DeficiencyRx – Iron Deficiency

Correct underlying cause – Menorrhagia, Correct underlying cause – Menorrhagia, MalabsorptionMalabsorption

Recommend Hysterectomy for fibroids Recommend Hysterectomy for fibroids with menorrhagia in a patient who has with menorrhagia in a patient who has completed her family.completed her family.

Oral Iron Supplements – preferredOral Iron Supplements – preferred Side effects oral iron – nausea, Side effects oral iron – nausea,

constipationconstipation If too many side effects and severe Fe If too many side effects and severe Fe

deficiency – consider Iron dextran IV deficiency – consider Iron dextran IV

Hereditary SpherocytosisHereditary Spherocytosis

Lack of central pallorLack of central pallor Osmotic Fragility test Osmotic Fragility test Rx : blood transfusions, splenectomyRx : blood transfusions, splenectomy Watch secondary hemochromatosis – Watch secondary hemochromatosis –

use Desferrioxamine use Desferrioxamine

A 32-year-old man of Italian descent is evaluated for a routine pre-employment physical examination. He has always been healthy, and his physical examination is normal.

Laboratory Studies Hematocrit 35% Mean corpuscular volume 63 fL Leukocyte count 6800/μL Reticulocyte count 40,000/μL (0.7% of erythrocytes) Platelet count 270,000/μL Results of fecal occult blood testing are negative. Peripheral blood smear

shows microcytosis and many target cells.

Which of the following is the best diagnostic test to evaluate the cause of the anemia and microcytosis?

( A ) Coombs' direct antiglobulin test ( B ) Measurement of hemoglobin A2 level ( C ) Glucose-6-phosphate dehydrogenase screen ( D ) Measurement of serum iron, total iron-binding capacity, and ferritin

levels

A 22-year-old female college student of Greek descent is evaluated because she tires easily and has had palpitations

when playing tennis for the past 3 months. She reports no night sweats or weight loss, and her family history is negative for anemia. She has two healthy siblings.Physical examination is unremarkable. A complete blood count shows a hemoglobin of 9.0 g/dL with a hematocrit of 28% and an erythrocyte count of 3.7 million/μL. Erythrocyte distribution width is elevated at 17% (normal range 10.5% to 14.5%). The neutrophil, lymphocyte, and platelet counts are normal.

Which of the following is the most appropriate initial step in the management of this patient?

( A ) Perform hemoglobin electrophoresis for hemoglobin A2 and F. ( B ) Perform complete blood counts for siblings. ( C ) Measure serum ferritin. ( D ) Perform ultrasonography of the spleen. ( E ) Perform Southern blot analysis

Key PointsKey PointsAn elevated erythrocyte distribution width is consistent with iron-deficiency anemia.

Measurement of serum ferritin can differentiate iron-deficiency anemia from the anemia of thalassemia trait.

Macrocytic AnemiasMacrocytic Anemias

Vitamin B12 defVitamin B12 def Folic acid defFolic acid def Alcohol/ ZidovudineAlcohol/ Zidovudine HypothyroidismHypothyroidism Subtle clues for Vit b12 def Subtle clues for Vit b12 def ataxia, ataxia,

neurological symps, psychosis, dementianeurological symps, psychosis, dementia Pernicious anemia – screen all B12 def pts Pernicious anemia – screen all B12 def pts

with anti-parietal cell abs. ( Rx is IM b12 with anti-parietal cell abs. ( Rx is IM b12 for life )for life )

Hemolytic AnemiasHemolytic Anemias Labs that suggest Hemolysis Labs that suggest Hemolysis Indirect Indirect

bilirubin, LDH, Reticulocyte count, bilirubin, LDH, Reticulocyte count, HaptoglobinHaptoglobin

Peripheral smear Peripheral smear help to r/o help to r/o microangiopathic hemolysis microangiopathic hemolysis (Schistocytosis), increased reticulocytes(Schistocytosis), increased reticulocytes

Urine Hemosiderin Urine Hemosiderin elevated only in elevated only in uintravascular hemolysisuintravascular hemolysis

Direct coomb +ve Direct coomb +ve Autoimmune Autoimmune Hemolysis.Hemolysis.

Concomitant thrombocytopenia may Concomitant thrombocytopenia may suggest TTP, DIC, EVANS syndromesuggest TTP, DIC, EVANS syndrome

Microangiopathic HemolysisMicroangiopathic Hemolysis

Characterized by schistocytosis – Characterized by schistocytosis – fragmented RBCs on peripheral fragmented RBCs on peripheral smearsmear

Seen in TTP, DIC, HUS, HELLP Seen in TTP, DIC, HUS, HELLP syndrome, CAPS, malignant syndrome, CAPS, malignant hypertensionhypertension

Macroangiopathic hemolysis – also Macroangiopathic hemolysis – also can have schistocytes eg: prosthetic can have schistocytes eg: prosthetic valves. valves.

Autoimmune Hemolytic AnemiasAutoimmune Hemolytic Anemias

Direct coombs +veDirect coombs +ve Microspherocytes on peripheral smearMicrospherocytes on peripheral smear Urine hemosiderin –veUrine hemosiderin –ve LDH elevated, Hapto may be lowLDH elevated, Hapto may be low Retic count increasedRetic count increased Rx : Steroids, IVIG, SplenectomyRx : Steroids, IVIG, Splenectomy Recognize Autoimmune hemolysis in CLL Recognize Autoimmune hemolysis in CLL

A 63-year-old man with stage I chronic lymphocytic leukemia (CLL) is evaluated for increasing dyspnea on exertion that has developed over the past 2 weeks. He currently takes no medications. On physical examination, he has pale conjunctivae and scattered axillary and inguinal lymphadenopathy that are unchanged from his last examination 1 year ago. His is afebrile. Pulmonary examination is normal except for tachypnea.

Laboratory Studies Hematocrit 18% Leukocyte count 12,000/μL (25% polymorphonuclear leukocytes, 75%lymphocytes) Platelet count 285,000/μL A peripheral blood smear shows spherocytes, a reticulocyte count of 10%,

polychromatophilia, smudge cells, and normal-appearing lymphocytes with no schistocytes. Hematocrit 1 year ago was 46%.

Which of the following is the most likely cause of this new onset of anemia? ( A ) Conversion of CLL to acute lymphoblastic leukemia ( B ) Autoimmune hemolytic anemia ( C ) Disseminated intravascular coagulation ( D ) Marrow infiltration by CLL ( E ) Conversion to a large-cell lymphoma (Richter's syndrome)

A 27-year-old black man is admitted to the hospital for treatment of community-acquired pneumonia, for which he received erythromycin. On the second hospital day, he is lethargic and has easy fatigability, a temperature of 38.4 °C (101.1°F), and scleral icterus. The patient had a similar episode during a childhood ear infection. His two brothers have had similar problems, though his sister has not. His hematocrit, which was 40% on admission, is now 32%. His reticulocyte count is 140,000/μL (4% of erythrocytes).Liver studies show a serum total bilirubin concentration of 5.4 mg/dL and a direct bilirubin concentration of 1.4 mg/dL.

A peripheral blood smear is shown. Which of the following is the most appropriate diagnostic

study at this time? ( A ) Sickling test ( B ) Glucose-6-phosphate dehydrogenase measurement ( C ) Hemoglobin electrophoresis ( D ) Erythrocyte pyruvate kinase activity measurement ( E ) No further testing

Key PointKey PointFollowing an acute hemolytic event due to

glucose-6-phosphate dehydrogenase deficiency (G6PD),G6PD levels will be normal. Testing

should be delayed for 3 to4 weeks.

AnemiasAnemias A 19-year-old woman comes to the student health service A 19-year-old woman comes to the student health service

complaining that since the new semester has begun, she finds complaining that since the new semester has begun, she finds herself unable to focus and concentrate as well as before. She herself unable to focus and concentrate as well as before. She attributes this largely to feeling fatigued. She denies any other attributes this largely to feeling fatigued. She denies any other symptoms such as sadness, sleeplessness, or loss of libido. She symptoms such as sadness, sleeplessness, or loss of libido. She has no other medical issues. Her medications are only oral has no other medical issues. Her medications are only oral contraceptive pills. She has never been pregnant and denies contraceptive pills. She has never been pregnant and denies current pregnancy. She has a history of long menses, often lasting current pregnancy. She has a history of long menses, often lasting 8 days. Laboratory studies show: 8 days. Laboratory studies show:

Hct 31%Hct 31% MCV 69um3MCV 69um3 Ferritin 10mcg/LFerritin 10mcg/L The most appropriate next step is toThe most appropriate next step is to

A. administer iron, intravenouslyA. administer iron, intravenously B. administer vitamin B12, intravenouslyB. administer vitamin B12, intravenously C. advise her to take folate tabletsC. advise her to take folate tablets D. change her oral contraceptive formulation to estrogen onlyD. change her oral contraceptive formulation to estrogen only E. tell her to take oral iron tabletsE. tell her to take oral iron tablets

AnemiasAnemias A 5-year-old boy is brought to the clinic for a periodic health maintenance A 5-year-old boy is brought to the clinic for a periodic health maintenance

examination. He is generally healthy, enjoys school, plays well with his examination. He is generally healthy, enjoys school, plays well with his siblings and with other children his age. He and his family live in a housing siblings and with other children his age. He and his family live in a housing development down the street that was built 10 years ago. Since his mother development down the street that was built 10 years ago. Since his mother usually works until late in the evening, he tends to spend a lot of time at a usually works until late in the evening, he tends to spend a lot of time at a friend's apartment in an old, dilapidated housing development nearby. You friend's apartment in an old, dilapidated housing development nearby. You notice that he has unusually pale skin and mucus membranes and so you notice that he has unusually pale skin and mucus membranes and so you inquire about related symptoms. The mother tells you that she has noticed inquire about related symptoms. The mother tells you that she has noticed that he is significantly more tired than his siblings and he has been a "bit that he is significantly more tired than his siblings and he has been a "bit irritable" lately but she "didn't think nothing of it." He is up-to-date on all irritable" lately but she "didn't think nothing of it." He is up-to-date on all of his immunizations. There is no family history of blood disorders, however of his immunizations. There is no family history of blood disorders, however several of his playmates "are anemic." You decide to order hemoglobin, several of his playmates "are anemic." You decide to order hemoglobin, hematocrit, and a peripheral blood smear and schedule a follow-up visit in 1 hematocrit, and a peripheral blood smear and schedule a follow-up visit in 1 week. He returns for his next appointment and you review the results of the week. He returns for his next appointment and you review the results of the laboratory studies. His hemoglobin is 9.5 g/dL, hematocrit is 30%, and the laboratory studies. His hemoglobin is 9.5 g/dL, hematocrit is 30%, and the peripheral blood smear shows microcytic red blood cells with basophilic peripheral blood smear shows microcytic red blood cells with basophilic stippling. The most appropriate next step is tostippling. The most appropriate next step is to

A. administer ferrous sulfate, orallyA. administer ferrous sulfate, orally B. administer dimercaprol, orallyB. administer dimercaprol, orally C. administer edetate disodium, orallyC. administer edetate disodium, orally D. determine B12 levelsD. determine B12 levels E. determine blood lead levelsE. determine blood lead levels F. obtain an abdominal radiographF. obtain an abdominal radiograph G. order hemoglobin electrophoresisG. order hemoglobin electrophoresis H. Check Erythrocyte Zinc Protoporphrin levelsH. Check Erythrocyte Zinc Protoporphrin levels

During a routine screening for mild dementia, a 78-year-old male resident of a nursing home is found to have a low serum vitamin B12 level. He does not have fatigue, dyspnea, chest pain, dizziness, unsteadiness, or paresthesias. His

medical history is significant for coronary artery disease, for which he underwent coronary stent placement 5 years ago. His medications include metoprolol and atorvastatin. Physical examination does not indicate any symptoms of vitamin B12 deficiency, such as glossitis or impaired sensation.

Laboratory Studies Hematocrit 43% Mean corpuscular volume 94 fL Serum creatinine 1.4 mg/dL Serum vitamin B12 level 200 pg/mL

Which of the following is the most appropriate next step in the management of this patient?

( A ) Weekly vitamin B12 injections ( B ) Intrinsic factor antibody test ( C ) Serum methylmalonic acid level ( D ) Schilling test

Subclinical B12 Subclinical B12 DeficiencyDeficiency

- May not have any symps- May not have any symps- Elevation of MMA is a sensitive - Elevation of MMA is a sensitive marker of significant deficiencymarker of significant deficiency

- Treat it!- Treat it!

Sickle Cell AnemiaSickle Cell Anemia Sickle cell trait/ Sickle cell anemiaSickle cell trait/ Sickle cell anemia Sickling test : sickle cell screenSickling test : sickle cell screen C/F:Sickle cell crisesC/F:Sickle cell crises Acute Chest syndromeAcute Chest syndrome InfectionsInfections DactylitisDactylitis Aplastic Crises : folic acid deficiency vs. Parvo virusAplastic Crises : folic acid deficiency vs. Parvo virus Avascular Necrosis hip Avascular Necrosis hip get MRI get MRI Labs : HGB electrophoresis, Peripheral smear – howell-jolley Labs : HGB electrophoresis, Peripheral smear – howell-jolley

bodies, stress lymphocytosis, increased retic count, anemia, bodies, stress lymphocytosis, increased retic count, anemia, hemolysis, elevated indirect bilirubinhemolysis, elevated indirect bilirubin

Management : Management : Acute pain crises Acute pain crises manage with IV Fluids, analgesics, septic manage with IV Fluids, analgesics, septic

w/u, electrolyte repletion, watch for substance abusers ( clues w/u, electrolyte repletion, watch for substance abusers ( clues are labs)are labs)

Recurrent Acute pain crises Recurrent Acute pain crises more than 3-4 episodes per more than 3-4 episodes per year, use Hydroxyurea. D/W pt benefits vs. toxicity of hydreayear, use Hydroxyurea. D/W pt benefits vs. toxicity of hydrea

Acute Chest Syndrome Acute Chest Syndrome O2, analgesics, Exchange O2, analgesics, Exchange TransfusionTransfusion

A 17-year-old male patient with homozygous sickle cell anemia was admitted to the hospital for hydration and analgesia of a painful crisis. On hospital day 3, his condition deteriorated, with the onset of fever, new chest pain, and dyspnea. On physical examination, he has a temperature of 38.9 °C (102 °F), pulse rate of 120/min, and respiration rate of 32/min. He is using accessory muscles of inspiration and has crackles bilaterally. Chest radiographs show new, bilateral pulmonary infiltrates and a normal-sized heart. Pulse oximetry shows an oxygen saturation rate of 80% on room air. Which of the following is the most important immediate therapeutic option?

( A ) Amoxicillin ( B ) Hydroxyurea ( C ) Diuretics and digoxin ( D ) Partial-exchange transfusion ( E ) Polyvalent pneumococcal vaccine

Key pointKey pointThe acute chest syndrome is characterized by chest pain, fever, diffuse pulmonary infiltrates, and hypoxia in a patient with sickle cell anemia.

The most effective therapy for the acute chest syndrome in sickle cell anemia is partial-exchange transfusion to lower the hemoglobin S.

Splenectomy Splenectomy Prior to splenectomy Patients should Prior to splenectomy Patients should

be immunized with pneumococcal, be immunized with pneumococcal, HIB and meningococcal vaccinesHIB and meningococcal vaccines

Daily oral penicillin prophylaxis for Daily oral penicillin prophylaxis for splenectomized patients.splenectomized patients.

A 56-year-old man is evaluated for fatigue during a routine office visit. His history is significant for diverticulosis,hypertension, and supraventricular tachycardia, for which he takes aspirin, metoprolol, and ramipril. On physical examination, he is afebrile, his blood pressure is 120/80 mm Hg, and pulse rate is 80/min. No abdominal tenderness,splenomegaly, or lymphadenopathy is noted.

Laboratory Studies Hemoglobin 8 g/dL Mean corpuscular volume 76 fL Leukocyte count 11,200/μL Platelet count 847,000/μL

Which of the following is the most appropriate next diagnostic test for this patient?

( A ) Fluorescence in situ hybridization analysis of blood for Philadelphia chromosome ( B ) Examination of bone marrow aspirate ( C ) Serum ferritin measurement and fecal occult blood testing ( D ) Repeated complete blood count in 2 weeks after discontinuation of all current

medications ( E ) Bleeding-time measuremen

Ans. Reactive ThrombocytosisAns. Reactive Thrombocytosis Iron deficiencyIron deficiency MalignancyMalignancy Major SurgeryMajor Surgery Acute blood lossAcute blood loss Primary thrombocytosis can be caused by clonal disorders, such

as chronic myelogenous leukemia (CML), polycythemia vera, and essential thrombocythemia. CML is characterized by the presence of the Philadelphiachromosome in blood and marrow myeloid cells. Patients with CML typically have a high leukocyte count, high or normal platelet and erythrocyte counts, and splenomegaly. The absence of leukocytosis and splenomegaly and thepresence of severe microcytic anemia make CML unlikely

Essential thrombocythemia may be associated with thrombotic and hemorrhagic complications. Patients with essential thrombocythemia have a platelet count of greater than 600,000/μL without known causes for reactive thrombocytosis; therefore, iron deficiency precludes this diagnosis.

Bleeding DisordersBleeding Disorders

A 48-year-old female nurse is evaluated for hematuria. One week ago, she experienced dysuria, for which cephalothin was prescribed. Her history is remarkable only for an uneventful tonsillectomy as a child and removal of a benign ovarian cyst at age 36; there is no family history of bleeding. The patient does not smoke or use alcohol or recreational drugs. She has a normal diet, and her weight has been stable. She has a history of depression that has been treated with numerous antidepressants, but she is not taking any medications currently. On physical examination, she has two ecchymoses on her lower extremities. Laboratory evaluation includes a prothrombin time (PT) of 28.2 sec (INR 4.2), activated partial thromboplastin time (PTT) of 45 sec (normal < 35 sec), normal thrombin time, negative D-dimer, and normal complete blood count and platelet count. Liver enzymes are within normal limits, and serum albumin is 4.1 g/dL. An inhibitor-screen mixing study shows complete correction of the PT and PTT after mixing of patient and control plasma at a 1:1 ratio. The factor VII level is 6%, factor IX level is 10%, factor VIII level is 110%, and factor V level is 95% (reference range 60% to 150%).

Which of the following is the most likely diagnosis? ( A ) Acquired factor VIII inhibitor ( B ) Lupus anticoagulant ( C ) Hemophilia B (Christmas disease) ( D ) Surreptitious warfarin ingestion

Key Point Key Point In severe vitamin K deficiency, the prothrombin time and the Partial thromboplastin time are prolonged.In mild vitamin K deficiency (including therapeutic warfarin), only the prothrombin time is prolonged

Von Willebrands Von Willebrands DiseaseDisease

Screen for VWdScreen for VWd Screen for VWD in women with menorrhagia and no Screen for VWD in women with menorrhagia and no

gynecologic reason for heavy bleeding, in patients with gynecologic reason for heavy bleeding, in patients with unexplained procedural bleeding, and in individuals with a unexplained procedural bleeding, and in individuals with a personal or family history or physical evidence of personal or family history or physical evidence of mucocutaneous bleeding.mucocutaneous bleeding.

Remember VWd can be asymptomatic for a long time with Remember VWd can be asymptomatic for a long time with no hx at all and may just present with excess bleeding no hx at all and may just present with excess bleeding during surgical proceduresduring surgical procedures

Conduct a first-line coagulation screening work-up, Conduct a first-line coagulation screening work-up, including PT, PTT, CBC/platelets, and thrombin time. including PT, PTT, CBC/platelets, and thrombin time. If If PTT is prolonged and other initial test results are normal, PTT is prolonged and other initial test results are normal, suspect VWD as a possible diagnosis ( BT is prolonged too. suspect VWD as a possible diagnosis ( BT is prolonged too. BT is N in Hemophilia ) ( Remember d/d for isolated PTT BT is N in Hemophilia ) ( Remember d/d for isolated PTT prolongation is also thrombotic condition APLA/ LA – This prolongation is also thrombotic condition APLA/ LA – This manifests by thrombosis though, unlike VWd which is manifests by thrombosis though, unlike VWd which is bleeding) bleeding)

Initial tests for the diagnosis or exclusion of VWD include Initial tests for the diagnosis or exclusion of VWD include VWF function, VWF:Ag, and factor VIII activity and should be VWF function, VWF:Ag, and factor VIII activity and should be done more than once. done more than once.

Rx - VWdRx - VWd

In treatment of significant bleeding In treatment of significant bleeding events or for prevention of bleeding events or for prevention of bleeding during invasive procedures or during invasive procedures or surgeries surgeries use Desmopressin use Desmopressin

Remember Tachyphylaxis with Remember Tachyphylaxis with desmopressin ( in case of continued desmopressin ( in case of continued bleeding after desmopressin , use bleeding after desmopressin , use Cryoprecipitate/ VWF concentrate) Cryoprecipitate/ VWF concentrate)

Uremic BleedingUremic Bleeding

Bleeding time is the best predictor Bleeding time is the best predictor for tendency to bleed.for tendency to bleed.

Desmopressin – Rx of choice in Desmopressin – Rx of choice in preventing bleeding for surgical preventing bleeding for surgical procedures or in Rx of Bleedingprocedures or in Rx of Bleeding

Conjugated EstrogensConjugated Estrogens Blood transfusion to keep hct high Blood transfusion to keep hct high Recombinant Factor VIIaRecombinant Factor VIIa

HemophiliaHemophilia

Screen for hemophilia A and B in individuals with: Screen for hemophilia A and B in individuals with: A history of bleeding A history of bleeding Family members known to have hemophilia or be Family members known to have hemophilia or be

hemophilia carriers hemophilia carriers Unexplained aPTT prolongation ( BT normal) Unexplained aPTT prolongation ( BT normal) DX : If APTT prolonged, do mixing study. Correction DX : If APTT prolonged, do mixing study. Correction

suggests Factor deficiency. suggests Factor deficiency. Then obtain quantitative factor VIII/ IX levels and activity.Then obtain quantitative factor VIII/ IX levels and activity. In patients with prolonged PTT and decreased factor VIII In patients with prolonged PTT and decreased factor VIII

activity who have no family hx of hemophilia a, obtain VWF activity who have no family hx of hemophilia a, obtain VWF level to r/o VWdlevel to r/o VWd

Hemophilias can present with deep bleeding ( Hemarthrosis) Hemophilias can present with deep bleeding ( Hemarthrosis) apart from superficial bleeding ( mucosal bleeding, apart from superficial bleeding ( mucosal bleeding, ecchymoses, bruises with minimal trauma)ecchymoses, bruises with minimal trauma)

RX: factor VIII/ IX concentrates ( A – Factor VIII def, B – FACTOR RX: factor VIII/ IX concentrates ( A – Factor VIII def, B – FACTOR ix DEF)ix DEF)

ThrombocytopeniasThrombocytopenias

ThrombocytopeniasThrombocytopenias Drug Induced : HIT, GP IIb IIIA inhibitors Drug Induced : HIT, GP IIb IIIA inhibitors

( abciximab, eptifibitide), ( abciximab, eptifibitide), LinezolidLinezolid, , ClopidogrelClopidogrel

Always r/o Pseudothrombocytopenia – this Always r/o Pseudothrombocytopenia – this is our first step.is our first step.

Congenital thrombocytopenia ( Some are Congenital thrombocytopenia ( Some are microthrombocytopenias)microthrombocytopenias)

Consumption Thrombocytopenias : TTP, Consumption Thrombocytopenias : TTP, DIC, Massive Bleeding, SepsisDIC, Massive Bleeding, Sepsis

ITP ITP ITP + AIHA ( Coombs +ve, Evans ITP + AIHA ( Coombs +ve, Evans

syndrome)syndrome)

Platelet transfusions - IndicationsPlatelet transfusions - Indications

Platelets < 15kPlatelets < 15k Platelets<50k + ICH/Life threatening Platelets<50k + ICH/Life threatening

hemorrhagehemorrhage Platelets > 50k Platelets > 50k no platelets ( all we no platelets ( all we

need is 50k platelets for enough clotting. need is 50k platelets for enough clotting. So, no need of transfusions for So, no need of transfusions for platelets>50k)platelets>50k)

Avoid platelets in TTP/ DIC unless severe Avoid platelets in TTP/ DIC unless severe bleeding which is unlikely manifestatuion bleeding which is unlikely manifestatuion in these cases.in these cases.

Idiopathic thrombocytopenic purpuraIdiopathic thrombocytopenic purpura

Previous CBC is a cluePrevious CBC is a clue Rule out other causes – drugs, liver disease, HIV, HEP-C, APLA, SLE Rule out other causes – drugs, liver disease, HIV, HEP-C, APLA, SLE

etc etc HIV related ITP responds to HAART/ Zidovudine most studied.HIV related ITP responds to HAART/ Zidovudine most studied. Rx – mild ITP is often associated with a good prognosis. Rx – mild ITP is often associated with a good prognosis. Platelet counts >50 × 109 cells/L with no history of bleeding Platelet counts >50 × 109 cells/L with no history of bleeding

careful observation with regular visits and platelet count careful observation with regular visits and platelet count determinations determinations

Prednisone f Plts < 30k Prednisone f Plts < 30k If there is a response with a If there is a response with a normalization of the platelet count over 1 to 2 weeks, taper by 5 to normalization of the platelet count over 1 to 2 weeks, taper by 5 to 10 mg/week. 10 mg/week.

IVIG if immediate response is required i.e; before surgical IVIG if immediate response is required i.e; before surgical procedures, or in initial treatment for patients with severe bleeding procedures, or in initial treatment for patients with severe bleeding AND also, in patients who are refractory to treatment with AND also, in patients who are refractory to treatment with glucocorticoids. Remember, response short-lived.glucocorticoids. Remember, response short-lived.

Consider RhIG as outpatient therapy: In patients who are Rh(+) and Consider RhIG as outpatient therapy: In patients who are Rh(+) and have not had a splenectomy , For patients in whom splenectomy is have not had a splenectomy , For patients in whom splenectomy is not feasible and along with IVIG in patients in whom steroids have not feasible and along with IVIG in patients in whom steroids have failed failed

Splenectomy if no response to steroids (persistent platelet counts Splenectomy if no response to steroids (persistent platelet counts <10 × 109 cells/L for 4 to 6 weeks and for patients who have had <10 × 109 cells/L for 4 to 6 weeks and for patients who have had ITP for 3 months with persistent severe thrombocytopenia (platelet ITP for 3 months with persistent severe thrombocytopenia (platelet count <30 × 109 cells/L) despite treatment) or count <30 × 109 cells/L) despite treatment) or Relapse after Relapse after tapering Steroidstapering Steroids

Can try immunosuppressants (AZA) or Rituximab if Can try immunosuppressants (AZA) or Rituximab if splenectomy and Steroids are unsuccessfulsplenectomy and Steroids are unsuccessful

HITHIT Usually occurs with in 5-7 days after exposure to heparin.Usually occurs with in 5-7 days after exposure to heparin. Immediate HIT is possible if there was prior exposure in Immediate HIT is possible if there was prior exposure in

past 3 months enabling circulating antibodiespast 3 months enabling circulating antibodies Heparin induced Anti-platelet Abs Heparin induced Anti-platelet Abs screening test screening test Serotonin Release Assay Serotonin Release Assay confirmatory test confirmatory test Base your decision most on clinical probability rather than Base your decision most on clinical probability rather than

these tests.these tests. Features Features deep vein thrombosis, PE, Arterial thrombosis in deep vein thrombosis, PE, Arterial thrombosis in

a setting of acute thrombocytopenia after exposure to a setting of acute thrombocytopenia after exposure to heparin.heparin.

Rx Rx Once HIT is suspected/ diagnosed , must be treated Once HIT is suspected/ diagnosed , must be treated Rx Rx Argatroban, leperidin overlap with warfarin Argatroban, leperidin overlap with warfarin Lepiridin difficult to monitorLepiridin difficult to monitor Argatroban adds to INR. So, safely discontinued after Argatroban adds to INR. So, safely discontinued after

warfarin started and INR of 4.0 is reached. Repeat INR in 6 warfarin started and INR of 4.0 is reached. Repeat INR in 6 hrs after discontinuing Argatroban hrs after discontinuing Argatroban to confirm therapeutic to confirm therapeutic range INRrange INR ( 2 to 3) ( 2 to 3)

Case StudyCase Study A 67 y/o man in previously good health is A 67 y/o man in previously good health is

hospitalized with 2 day hx of fever and decreased hospitalized with 2 day hx of fever and decreased consciousness. Temp is 103 F, HR 140, BP 88/50. consciousness. Temp is 103 F, HR 140, BP 88/50. There is no bleeding. The hgb 12.1 gm%, wbc There is no bleeding. The hgb 12.1 gm%, wbc 29,000, platelets 20,000/ul. Which of the 29,000, platelets 20,000/ul. Which of the following should be obtained next?following should be obtained next?

A) Bone marrow biopsyA) Bone marrow biopsy B) Factor VIII levelB) Factor VIII level C) Measurement of platelet associated IgGC) Measurement of platelet associated IgG D) Measurement of D-Dimer and fibrinogenD) Measurement of D-Dimer and fibrinogen E) Bleeding timeE) Bleeding time

AnemiasAnemias A 21-year-old man with no significant past medical history A 21-year-old man with no significant past medical history

presents to office with complaints of blood in his urine and presents to office with complaints of blood in his urine and mucosal bleeding while brushing his teeth. He denies any drug or mucosal bleeding while brushing his teeth. He denies any drug or alcohol use. He has no family history of bleeding disorders. alcohol use. He has no family history of bleeding disorders. Petechiae are noted in the oral cavity, as is dried blood in the Petechiae are noted in the oral cavity, as is dried blood in the nostrils. Laboratory studies show the following: Hematocrit 32%; nostrils. Laboratory studies show the following: Hematocrit 32%; white blood cell count 8,000/mm3 with 60% neutrophils; platelet white blood cell count 8,000/mm3 with 60% neutrophils; platelet count 13,000; PT 13 seconds; PTT 28 seconds; LDH 1,200 U/L; count 13,000; PT 13 seconds; PTT 28 seconds; LDH 1,200 U/L; elevated indirect bilirubin. Coombs' test is positive; abdominal elevated indirect bilirubin. Coombs' test is positive; abdominal examination is normal; and the peripheral smear shows examination is normal; and the peripheral smear shows spherocytes.spherocytes.

What is the most likely diagnosis?What is the most likely diagnosis?

(A) Gordon's syndrome(A) Gordon's syndrome(B) Bernard-Soulier syndrome(B) Bernard-Soulier syndrome(C) Felty's syndrome(C) Felty's syndrome(D) Thrombotic thrombocytopenic purpura(D) Thrombotic thrombocytopenic purpura(E) Evans' syndrome(E) Evans' syndrome(F) Idiopathic thrombocytopenic purpura (ITP)(F) Idiopathic thrombocytopenic purpura (ITP)

Myeloproliferative DisordersMyeloproliferative Disorders

Polycythemia vera ( differentiate Polycythemia vera ( differentiate from secondary polycythemia)from secondary polycythemia)

Essential thrombocytosisEssential thrombocytosis CMLCML Myelofibrosis ( “tear drop” cells)Myelofibrosis ( “tear drop” cells)

Polycythemia VeraPolycythemia Vera Measure RBC mass to r/o relative polycythemiaMeasure RBC mass to r/o relative polycythemia Differentiate from Secondary polycythemia – R/o Differentiate from Secondary polycythemia – R/o

hypoxia which is the most common cause.hypoxia which is the most common cause. Presence of leucocytosis and thrombocytosis as Presence of leucocytosis and thrombocytosis as

well as spelenomegaly are big clues that this well as spelenomegaly are big clues that this could be primary.could be primary.

EPO levelEPO level JAK-2 mutationJAK-2 mutation Pruritis during shower often seen in primary Pruritis during shower often seen in primary

polycythemia due to histamine release from mast polycythemia due to histamine release from mast cellscells

Bone marrow biopsy if EPO is low or normal in Bone marrow biopsy if EPO is low or normal in presence of polycythemiapresence of polycythemia

Secondary PolycythemiaSecondary Polycythemia R/o Relative Polycythemia secondary to R/o Relative Polycythemia secondary to

hemoconcentration/ dehydration hemoconcentration/ dehydration repeat repeat CBC after HydrationCBC after Hydration

Chronic Hypoxia : COPD, high altitudes, Chronic Hypoxia : COPD, high altitudes, OSA, Obesity hypoventilation, intra-cardiac OSA, Obesity hypoventilation, intra-cardiac shunts, smoking shunts, smoking EPO elevated/ normal EPO elevated/ normal

Neoplasms : RCC, Pheochromocytoma, Neoplasms : RCC, Pheochromocytoma, Cushings disease, cerebellar Cushings disease, cerebellar hemangioblastoma, hepatomahemangioblastoma, hepatoma

Endocrine : Cushings diseaseEndocrine : Cushings disease

C/F and RxC/F and Rx Pruritis in Polycythemia veraPruritis in Polycythemia vera Ruddish complexion, erythematous rashes on Ruddish complexion, erythematous rashes on

abdomen, extremities, purpura.abdomen, extremities, purpura. Pts have increased risk of both thrombosis and Pts have increased risk of both thrombosis and

bleeding bleeding Phlebotomy to keep hct < 45%Phlebotomy to keep hct < 45% Patients with symptomatic polycythemia should Patients with symptomatic polycythemia should

undergo immediate Phlebotomyundergo immediate Phlebotomy Headache, Dizziness, chestpainHeadache, Dizziness, chestpain Blurred vision, papilledema, hypertensive Blurred vision, papilledema, hypertensive

emergencies are indication for immediate emergencies are indication for immediate Phlebotomy.Phlebotomy.

Begin cytoreductive therapy concomitantly with Begin cytoreductive therapy concomitantly with phlebotomy in cases of P.Vera (Hydroxyurea).phlebotomy in cases of P.Vera (Hydroxyurea).

Hematological MalignanciesHematological Malignancies

Leukemias – ALL, AML, CML, CLLLeukemias – ALL, AML, CML, CLL Know when to treat CLL ( Anemia, Know when to treat CLL ( Anemia,

thrombocytopenia, Rx – Fludaribine, thrombocytopenia, Rx – Fludaribine, Chlorambucil) Chlorambucil)

CML – Studies, RxCML – Studies, Rx AML AML Know M3, associations and Rx Know M3, associations and Rx Lymphomas Lymphomas Hodgkins, NHL Hodgkins, NHL Secondary malignancies after Secondary malignancies after

radiotherapy ( Hodgkins survivors ) radiotherapy ( Hodgkins survivors ) follow up mammogramsfollow up mammograms

Peripheral smear

AnsAns

Plasma cell/ eccentric nucleusPlasma cell/ eccentric nucleus

Multiple MyelomaMultiple MyelomaD/DD/D

MGUSMGUSSolitary PlasmocytomaSolitary Plasmocytoma

POEMS syndrome (peripheral neuropathy, organomegaly, POEMS syndrome (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes, as well as endocrinopathy, monoclonal gammopathy, skin changes, as well as

other paraneoplastic features and osteosclerotic lesions) other paraneoplastic features and osteosclerotic lesions) Waldenström macroglobulinemia Waldenström macroglobulinemia

MGUSMGUS

M-Protein < 3gm%M-Protein < 3gm% Bone Marrow plasma cells < 10%Bone Marrow plasma cells < 10% Normal hgb, creatinine and serum calciumNormal hgb, creatinine and serum calcium Normal bone survey ( x-rays not bone Normal bone survey ( x-rays not bone

scan) scan) RX : may progress to MM. There’s no RX : may progress to MM. There’s no

evidence that chemotherapy reduces evidence that chemotherapy reduces progression – so don’t treat progression – so don’t treat

ObservationObservation

Solitary plasmacytomaSolitary plasmacytoma

Single lytic lesion in the boneSingle lytic lesion in the bone No evidence of anemia, renal No evidence of anemia, renal

insufficiency or high calciuminsufficiency or high calcium M-protein may or may not be M-protein may or may not be

elevatedelevated 75% progression to MM in 10 yrs75% progression to MM in 10 yrs No chemotherapy is recommendedNo chemotherapy is recommended Rx is excision and RadiationRx is excision and Radiation

Smoldering MyelomaSmoldering Myeloma

CharacteristicsCharacteristics• Serum M protein >3 g/dL and/or bone marrow Serum M protein >3 g/dL and/or bone marrow

plasma cells ≥10%plasma cells ≥10%• Absence of anemia, renal failure, Absence of anemia, renal failure,

hypercalcemia, lytic bone lesionshypercalcemia, lytic bone lesions Disease ManagementDisease Management

• Observation with treatment beginning at Observation with treatment beginning at disease progressiondisease progression

• BisphosphonatesBisphosphonates• Supportive careSupportive care• Participation in clinical trialParticipation in clinical trial

Symptomatic MMSymptomatic MM

Patients with symptomatic myeloma Patients with symptomatic myeloma require immediate treatment. require immediate treatment.

CharacteristicsCharacteristics• Presence of serum/urine M protein > 3gm%Presence of serum/urine M protein > 3gm%• Bone marrow plasmacytosis (usually >30%)Bone marrow plasmacytosis (usually >30%)• SYMPTOMS+SYMPTOMS+ Anemia, renal failure, Anemia, renal failure,

hypercalcemia, or lytic bone lesionshypercalcemia, or lytic bone lesions Treatment — Thalidomide + dexa, Treatment — Thalidomide + dexa,

lenalidomide, Melphalan lenalidomide, Melphalan

Waldenstroms MacroglobulinemiaWaldenstroms MacroglobulinemiaIncidence and clinical featuresIncidence and clinical features

Increased IgM. IgG may be decreased Increased IgM. IgG may be decreased 1,500 cases/year in USA1,500 cases/year in USA Median age -, 63 yrsMedian age -, 63 yrs Presenting symptomsPresenting symptoms

• Weakness and fatigueWeakness and fatigue 44%44%

• Hemorrhagic manifestationsHemorrhagic manifestations 44%44%

• Weight lossWeight loss 23%23%

• Neurologic symptomsNeurologic symptoms 11%11%

• Visual disturbancesVisual disturbances 8% 8%

• Raynauds phenomenonRaynauds phenomenon 3% 3%

Waldenstroms Macroglobulinemia:Waldenstroms Macroglobulinemia:Clinical FeaturesClinical Features

Tumor infiltrationTumor infiltration• Bone marrowBone marrow 90%90%• SplenomegalySplenomegaly 38%38%• LymphadenopathyLymphadenopathy 30%30%

Circulating IgMCirculating IgM• Hyperviscosity syndromeHyperviscosity syndrome• CryoglobulinemiaCryoglobulinemia• Cold agglutinin diseaseCold agglutinin disease• Bleeding disordersBleeding disorders

Tissue IgMTissue IgM• NeuropathyNeuropathy

Waldenstorms macroglobulinemiaWaldenstorms macroglobulinemia

Symptoms of hyperviscocity syndrome ( Headache, Symptoms of hyperviscocity syndrome ( Headache, chestpain, sob, blurred vision, papilledema)chestpain, sob, blurred vision, papilledema)

Rx: Rx: Plasmapheresis for circulating IgM complicationsPlasmapheresis for circulating IgM complications Alkylating-agent based therapy (50-70% response rate)Alkylating-agent based therapy (50-70% response rate)

• Chlorambucil and prednisoneChlorambucil and prednisone• CyclophosphamideCyclophosphamide• MelphalanMelphalan• CHOP (Cyclophosphomide, adriamycin, vincristine, prednisone)CHOP (Cyclophosphomide, adriamycin, vincristine, prednisone)

Nucleoside analogues (80-90% response rate)Nucleoside analogues (80-90% response rate) - Fludarabine- Fludarabine - 2-Chloro-deoxyadenosine (2-CdA)- 2-Chloro-deoxyadenosine (2-CdA)

Hematological EmergenciesHematological Emergencies

TTPTTP LEUCOSTASIS ( CML, AML)LEUCOSTASIS ( CML, AML) Acute Tumor Lysis SyndromeAcute Tumor Lysis Syndrome HITHIT Hyperviscocity SyndromeHyperviscocity Syndrome

Transfusion MedicineTransfusion Medicine

Transfusion ReactionsTransfusion Reactions

Febrile non hemolytic reactionsFebrile non hemolytic reactions Acute hemolytic transfusion reactionsAcute hemolytic transfusion reactions Delayed hemolytic transfusion Delayed hemolytic transfusion

reactionsreactions Anaphylactic reactionsAnaphylactic reactions Urticarial reactionsUrticarial reactions TRALITRALI Post transfusion purpuraPost transfusion purpura Graft versus host diseaseGraft versus host disease

Case StudyCase Study A 43 y/o m with severe acquired aplastic anemia A 43 y/o m with severe acquired aplastic anemia

has not responded to immunosuppressive agents. has not responded to immunosuppressive agents. He has a HLA identical brother who has been He has a HLA identical brother who has been cleared as a donor for his planned allogeneic cleared as a donor for his planned allogeneic stem cell transplant. They are both CMV negative. stem cell transplant. They are both CMV negative. Which of the following will be prevented by using Which of the following will be prevented by using irradiated cellular blood products to this patient?irradiated cellular blood products to this patient?

A) Graft versus Host disease, Transfusion relatedA) Graft versus Host disease, Transfusion related B) CMV diseaseB) CMV disease C) AlloimmunizationC) Alloimmunization D) Hemolytic transfusion reactionD) Hemolytic transfusion reaction E) Febrile non hemolytic transfusion reactionE) Febrile non hemolytic transfusion reaction

A 57-year-old woman (gravida 5, para 5) was admitted to the hospital with a bleeding duodenal ulcer for which she was given three units of packed erythrocytes. A regimen of antacids and cimetidine was initiated, and the patient was discharged after 3 days. Two days later, she returns to the hospital because of weakness, increased malaise, and dark urine. Her hematocrit, which was 37% at discharge, is now 26%. Liver studies show a total serum bilirubin of 6.1 mg/dL, with a direct value of 2.3 mg/dL, and a lactate dehydrogenase concentration of 467 U/L. Renal function is normal. Stools and a gastric lavage are negative for blood. The peripheral blood smear shows numerous microspherocytes.

Which of the following is the most appropriate next step in the management of this patient?

( A ) Corticosteroid therapy ( B ) Blood typing re-evaluation and cross-match ( C ) Osmotic fragility test ( D ) High-dose immunoglobulin infusion ( E ) Emergency surgical consultation

Key pointsKey points1. A delayed hemolytic transfusion reaction occurs

several dayS after transfusion and is characterized by an elevated serum lactate dehydrogenase level and a high indirect bilirubin level along with decreasing hematocrit and the presence of microspherocytes.

2. A repeated cross-match is likely to detect antibodies missed on the original cross-match.