Hematologic Emergencies

Tarek Elrafei, D.O.Hematology/Medical Oncology

Hem/Onc Emergencies• Crises in sickle cell

disease• Management of

transfusion reactions• TTP • DIC • Cytopenia or

Hyperleukocytosis– Febrile neutropenia– Acute leukemia with

Hyperleukocytosis

• Metabolic– Hypercalcemia– Tumor lysis syndrome

• Compressive or Obstructive syndromes– Spinal Cord compression– SVC syndrome– Urologic– Pericardial– Central airway

Sickle Cell Disease

• Which hemoglobin phenotype(s) are associated with ACS?

• Are there any laboratory/diagnostic tests that can screen for ACS?

• What is the best treatment modality for severe crises – simple vs exchange transfusion?

Chest 2000 May; 117(5):1386-92NEJM 2000; 342:1855-65

COMPLICATIONS IN SCD

• Acute painful crises• Acute chest syndrome (ACS)• Renal complications• Stroke• Ostenecrosis of the head of the femur/humerus• Sickle sequestration in the liver• Sickle sequestration in the spleen• Leg ulcers• Priapism

PRESENTATION OF ACS• New infiltrate

– pleural effusion (56%)AND…• Chest pain, cough, tachypnea, or

wheezing OR• Fever > 38.5• Drop in Hb (< 2g) and platelets

(<175,000)

Vichinsky et al, NEJM: 342;25. 1855-1865

Differentiating Acute Chest Syndrome vs. Pneumonia in SCD

• Low yield of bacterial diagnosis, even with broncoscopy and lavage.

• Involvement of basal lobes and bilateral• Dramatic effect of exchange transfusion• In SCD, but not in other patients, sickle

cells are trapped on the alveoli wall, become deoxygenated and incapable of exiting.

Other characteristics of ACS

• Most common cause of death in SCD young adults in spite that it is treatable complication.

• Second most common cause of hospitalization,.• Preceded or followed by acute painful crises.• After first ACS, repeat episodes are common• ACS can lead to pulmonary hypertension.

Etiology• Fat embolism

Alveolar macrophages in 77% who had BAL

• Viral: RSV, Parvo, Influenza, HSV, Echo, Rhino, CMV, EBV

• Atypical bacteria: Mycoplasma, Atypical Mycoplasma, Chlamydia,

Mycobacterium

• Bacteria:

Coag +Staph, Strep pneumonia,H Influenza, Legionella, pseudomonas, H Para-influenza, enterobacter, Klebsiella, Branhamella Catarrhalis, Serratia.

• 23-62% unknown

FAT EMBOLI PRESENTATION

• The most severe form of ACS, with longer hospital stays and high mortality when misdiagnosed.– Lower mean oxygen saturation– Higher incidence of vaso-occlusive events

• Fat emboli originate in marrow undergo infarct/necrosis with release of a combination of fat and hemopoietic precursors into the circulation.

• Unique is the trapping of fat/cells in lung alveoli and sometimes the brain (confusion and mini- strokes/hypoxia by imaging)

• Frequently associated with sternal pain.

Is there a reliable screening test to predict impending ACS?

Secretory Phospholipase A2 (sPLA2)

• sPLA2 is a potent inflammatory mediator– sPLA2hydrolysis of phospholipidsacute lung injury– ACS patients have sPLA2 levels which correlate with

severity of lung injury– SPLA2 rise occurs 24-48 hours prior to ACS – Transfusions rapidly lowers the plasma level of sPLA2 in

ACS. • “Increased levels of sPLA2 are capable of predicting

impending ACS, and qualify it as a screening tool.”

Styles et al. Blood. 1996;87: 2573-2578

Copyright ©2005 American Society of Hematology. Copyright restrictions may apply.

Bargoma, E. M. et al. Blood 2005;105:3384-3385

Figure 1. Day-by-day comparison of mean sPLA2 and CRP values in SCD patients (n=20) with VOC or ACS

Treatment of ACS• Treatment:

– Analgesics– Broad-spectrum antibiotics– Bronchodilator and incentive spirometry – Simple or exchange transfusion

• Simple: – when blood deoxygenation is not getting worse fast.

• Exchange: – When O2 sat is 87 or lower and falling within 6 hrs.– When patient is confused (fat emboli).– When sternal pain is present (fat emboli)

• Bronchoscopy is recommended in patients with no response to initial therapy

Summary

• Patients with any of the sickle cell disease Hgb phenotypes (SS, SC, S-ß thalassemia) can develop acute chest syndrome (ACS)

• ACS is predominantly a clinical diagnosis– New pulmonary infiltrate accompanied by fever, chest

pain or respiratory symptoms – usually preceded by VOC

• RBC Exchange transfusion may be life saving in severe cases

Transfusion Reactions

Risk of Blood Transfusion

• Infection• Transfusion related

– ABO Incompatible– Acute Lung Injury (TRALI)– Anaphylaxis– Circulatory Overload

• Total

• 5:10,000• 3:10,000

– 1:12,000– 1:10,000– 1:150,000– 1:10,000

• 8:10,000

U.S. Genreal Accounting Office, February 1997Blood Supply; Transfusion-Associated Risks (GAO/PEMD – 97-2)

Relative Risk of Transfusion Complications

Occurrence• Death from transfusion• Acute hemolytic reaction• HBV via transfusion• HCV• HIV• West Nile virus• Anaphylaxis• Annual risk of fatal accidents at home• MVA• Being murdered in Washington, D.C.

Risk• 1:100,000-200,000• 1:20,000• 1:50,000• 1:100,000-300,000• <1:1 Million

• 1:125,000• 1:10,000• 1:2,000• 1:2,155

Lee,Paling, Blajchman (1998) Transfusion, 37;184

Acute Hemolytic Transfusion Reactions

• MajorAB in recipient plasma + Donor RBC with

corresponding antigen• Minor

Antigen on recipient RBC + Donor AB• Interdonor

AB in donor X plasma + Antigen on donor Y RBC

Transfusion Reactions

• Symptoms– Chest tightness– SOB– Chills– Back pain– Hypotension– Burning at I.V.

Other Transfusion Reactions

• Allergic– IgA deficient individuals (1:550)– Can result in anaphylaxis

• Febrile– Bacterial contamination– Secondary to developing HLA Abs to

contaminating (donor) leukocytes

Transfusion Reactions Management

• Stop transfusion• Start IVF to avoid hypotension, shock, renal

failure• If oliguric (late phase) then may need fluid

restriction and lytes monitoring• Prevention

– 50% are a result of clerical errors

Transfusion Reaction Investigations

• Tbili & LDH – with hemolysis

• Urine – Hemoglobinuria when free Hgb > 25 mg/dL– Hemosiderinuria once plasma Hgb > 50 mg/dL

• Serum Haptoglobin with hemolysis because binds to free Hgb

• Coombs test• Blood type

TRALI• Defined as noncardiogenic pulmonary edema temporally related to the

transfusion of (plasma-containing) blood products• Mechanism: pulmonary leukoagglutinin reaction • Criteria for ALI *

1. Acute onset of lung injury (1-6 hours after transfusion)2. Measured PA occlusion pressure ≤18 mm Hg or a lack of clinical evidence

of left atrial hypertension (ie, no circulatory overload)3. Bilateral pulmonary infiltrates seen on frontal chest radiograph4. Hypoxemia: PaO2/FIO2 <300 mm Hg, or O2 saturation ≤90 percent on

room air• Symptoms include dyspnea, cough, and fever

– Onset Bilateral pulmonary infiltrates• Risk factors are cardiac disease and hematologic malignancy or a

predisposing inflammatory condition present in the OR or ICU• 5-8% mortality

*Transfusion 2004; 44:1774.

TRALI

TRALI Diagnostic Algorithm

- C he c k fe m a le do n ors for g ran u loc yte a n d H LA A b- I f fe m a le do n o rs ne g ative , ch eck m a le d on o rs

- D ete rm in e H L A a nd n eu trop h il a n tig e ns o f p a tie n ts- A n tib o d y-a n tige n cro ss m a tch

T R A LI s u sp e c ted- N o tify b lo o d b a nk

- K ee p re ce n tly tra n sfu se d b lo od ba g s a nd se n t to b lo od ba nk-d raw b lo od fro m p a tie n t a nd sen d to b lo od ba nk

R u le o u t ca rd io ge n ic p u lm o na ry e d em a a n d v o lum e o ve rlo ad- C lin ica l e x a m a n d C X R

-If n ee d e d e cho c ard io g ra p hy + /- p u lm o n ary a rte ry c a th e te riza t ion-If p re sen t, ob ta in u nd ilu te d pu lm o n ary e de m a flu id from tra c he a & m atc h ed p la s m a sam p le fo r p ro te in a n a lys is

S u spe c t TR A LI c a se(A L I in ju ry d ev e lo p in g d u ring tra n s fu s io n o r w ith in 6 h o f co m ple t ion

Chest. 2004 Jul;126(1):249-58.

TRALI Treatment

• Make the correct diagnosis• IV fluid administration• Supplemental oxygen/mechanical

ventilation• Diuretics relatively contraindicated• Glucocorticoids??

Summary

• Transfusion reactions may be due to incompatibility, IgA deficiency, allergy, or rarely bacterial contamination

• Major hemolytic transfusion reactions may progress to hypotension and shock

• Prevention should be aimed at minimizing unnecessary transfusions and eliminating clerical errors

TTP

• Is a syndrome of target-organ dysfunction caused by marked platelet aggregation in the microcirculation

• Explained by an acquired or inherited absence of VWf cleaving protease resulting in ULVWf– The plasma metalloprotease ADAMTS13 (A

Disintegrin And Metalloprotease with ThromboSpondin type 1 motif 13)

TTP Mechanism

TTP slide

Red Cell Fragmentation

• TraumaticProsthetic Heart ValvesMarch hemoglobinuria

• Infections Clostridia sepsisMalaria

• Microangiopathic

Microangiopathic Hemolytic Anemia

• Vasculitis• Malignant hypertension• Disseminated Intravascular Coagulation• Thrombotic Microangiopathies

– Hemolytic Uremic Syndrome– Eclampsia & HELLP Syndrome– Thrombotic Thrombocytopenic Purpura– Cancer-associated HUS

Treatment options for TTP

• Plasma exchangeCanadian Apheresis Study Group

N Engl J Med. 1991 Aug 8;325(6):393-7.

• Plasma infusion• NO platelet transfusion!• Immunosuppresion with corticosteroids• Antiplatelet drugs• Splenectomy• Rituximab

Apheresis in TTP

• Probably acts to supply vWF protease and remove its inhibitor

• Procedures are done daily• FFP is the replacement fluid• Endpoint is a normal platelet count, LDH

Venous Access

• Two large, durable peripheral veins• Central line with at least a dual lumen

– Femoral versus subclavian• Femoral increases thrombosis and infection• JAMA. 2001 Aug 8

Copyright restrictions may

.apply

Merrer, J. et al. JAMA 2001;286:700-707.

Complications of femoral and subclavian venous catheterization in critically ill patients

Infectious complications of central venous access

Complications of plasma exchange in 71 consecutive patients treated for clinically suspected thrombotic

thrombocytopenic purpura-hemolytic-uremic syndrome

Transfusion 40 (8), 896–901

Complications of Plasmapheresis related to central venous catheter access or plasma

• Twenty-one patients (30%) had 27 major complications, which caused two deaths.

• The major complications included 2 episodes of hemorrhage after subclavian line insertion (1 death), 1 pneumothorax requiring a chest tube, 12 systemic infections (1 death), – 7 episodes of catheter thrombosis requiring removal of the central

venous catheter, 2 episodes of venous thrombosis requiring anticoagulant treatment, 2 episodes of hypoxemia and hypotension, and 1 episode of serum sickness.

• Minor complications occurred in 22 additional patients (31%).

• Twenty-eight patients (39%) had no complications.

DIC

Disseminated Intravascular Coagulation (DIC)

• A heterogeneous group of clinicopathologic syndromes

• Characterized by dysregulated generation of thrombin (pathologic thrombin formation)

• Leading to intravascular fibrin formation, and• Secondary fibrinolysis (plasmin generation),• Often resulting in hemorrhage, thrombosis,

and/or multi-organ system failure

Routine Laboratory Investigation

• CBC, peripheral smear• PT/aPTT• Fibrinogen, thrombin clotting times• FDPs, fibrin D-dimer

Tests for DIC

D-dimer * FDP Platelet count Fibrinogen PT/INR aPTT

*more specific for DIC

• Highest Sensitivity

• Lowest Sensitivity

Specialized Tests

• Coagulation factor levels

• Natural anticoagulant levels:– Protein C, Protein S,

antithrombin• ‘Paracoagulation’

assays (e.g. protamine sulfate paracoagulation test)

• Molecular markers of:– Thrombin generation– Factor Xa generation– Thrombin action of

fibrinogen• Fibrinolytic system

– Plasminogen, -2 antipalsmin, PAI-1, etc

– Molecular markers of plasmin activation: plasmin-antiplasmin complexes, fibrin Bbeta-42 peptide

Some Causes of DIC• Infections

– Bacteremia– Rickettsial infections

• Metabolic disorders– Hypotension– Hypoxia– Hyper/hypothermia

• Obstetrical complications– Placental abruption– Placenta previa– Pregnancy-induced HTN– Amniotic fluid embolism– Retained dead fetus

• Vascular abnormalities

• Tumors– Adenocarcinoma– Tumor Lysis Syndrome– AML: M3(APL), M4 or M5

• Trauma– Crush injuries– Head injuries

• Toxins– Viper venom bites

• Drugs– L-asparaginase– Prothrombin complex concentrates– Heparin (via HIT)

Pathogenesis of DIC1. Depletion of hemostatic factors

– Hypofibrinogenemia (e.g., ‘defibrination’ syndrome, especially placental abruption and certain snakebites)

– Thrombocytopenia– Generalized depletion of multiple coagulation factors

2. Depletion of inhibitors– Potential for bleeding

• Depletion of 2-antiplasmin (unchecked plasmin action)– Potential for thrombosis

• Depletion of antithrombin (unchecked thrombin action)• Depletion of protein C/protein S (unchecked thrombin generation)

3. Heterogeneous ‘triggers’ of DIC

Pathogenesis of DIC: Heterogeneous triggers

• Systemic activation of hemostasis– Tissue thromboplastin (released by tissue injury, placental

abruption, tumors, etc.)– Cytokines (septicemia, inflammatory states)– Direct activator of Factor X (adenocarcinoma)– Prothrombin activation (Ecchis carinatus snake venom)– Procoagulant platelet membranes (HIT)– Endothelial injury or activation (infections, HIT)

• Localized activation of hemostasis– Abdominal Aortic Aneurysm– Giant hemangioma syndrome

Treatment of DIC: Special Situations

• Prohemorrhagic patients– Placental abruption:

obstetrical intervention, treat defibrination (cryoprecipitate)

– Prostate CA with hyperfibrinolysis:Replace fibrinogen (cryoprecipitate), antifibrinolytic

therapy (tranexamic acid, -aminocaproic acid)– Acute Promyelocytic Leukemia:

All-trans-retinoic acid (ATRA)

Treatment of DIC: Special Situations

• Prothrombotic patients– Adenocarcinoma (Trousseau’s syndrome):

Heparin, avoid warfarin

– Septicemia with acral gangrene (purpura fulminans):Vitamin K, heparin, FFP, recombinant activated protein C

concentrates (Drotrecogin alfa)

– Heparin-induced thrombocytopenia:Unusual DIC picture with increased thrombin generation

without low fibrinogen, PT, aPTT, THUS use agent that reduces thrombin generation (lepirudin, argatroban, danaproid)

Recombinant Human Activated Protein C

N Engl J Med. 2001 Mar 8;344(10):699-709. • 1960 patients

– Known infection– > 3 signs of systemic inflammation AND

sepsis-induced dysfuncion of one organ system• Drotrecogin alfa or placebo infusion• Relative risk reduction of death = 19.4%

(absolute reduction = 6.1%)• 3.5% vs 2% serious bleeding

Summary

• In SCD crises RBC exchange transfusion can be life saving

• Transfusion reactions– Hemolytic reactions can be due to incompatibility, IgA

deficiency, allergy, or rarely bacterial contamination of blood product

– The key to diagnosis and treatment of TRALI is a high clinical suspicion and the need to exclude cardiogenic pulmonary edema or volume overload

Summary

• TTP – Is a disorder of marked platelet aggregation which can

be worsened by platelet transfusion– Must differentiate from other causes of MAHA– Plasmapheresis is the treatment of choice

• DIC– Can manifest as uncontrolled bleeding, excessive

clotting, and/or multi-organ system failure– Treatment of underlying cause is of central importance.

Select cases may benefit from APCC