Hematology for Surgeons

Michael H. Rosove, MDClinical Professor of Medicine

UCLA Division of Hematology-Oncology

November 13, 2013

Anemias

Abrupt post-op drop in Hgb ― post-op equilibration, acute bleeding, or hemolysis

Sickle cell disorders

Thrombotic microangiopathies

Autoimmune and alloimmune hemolysis

Miscellaneous hemolytic anemias ― sepsis (especially Clostridium perfringens), liver disease, shear-related

Anemias

Sickle (Hgb S) disorders

Hgb SS > SC and S-β thalassemia > AS

Severity lessened by α-thalassemia minor, elevated Hgb F (hereditary persistence or hydroxyurea)

Problems: small vessel thrombotic occlusion (bone pain crisis, in situ pulmonary infarction, ischemic stroke, splenic or renal infarction), ↑ VTE risk

Management: avoid dehydration and hypoxemia, pre-op transfusion (to raise % Hgb A) in severe cases, VTE prophylaxis in appropriate settings

AnemiasThrombotic microangiopathies (TMAs)

Precapillary microvascular thrombosis, red cell fragmentation, thrombocytopenia, end-organ dysfunction/damage

TMA may follow organ transplantation ― especially kidney, lung, and allogeneic marrow stem cell transplantation

Target organ: Predominantly kidneys

Predisposing factors: Allograft rejection, infections, combined calcineurin and mTOR inhibitor therapies

Plasma exchange not known to be effective

? role for eculizumab (C5 inhibitor)

AnemiasAutoimmune hemolysisCauses: drugs, infectionsSpherocytosis (+ agglutination), DAT+, IgG + C3,

antibody screen or RBC eluate shows non-specific warm auto

Treatment: Dependent on cause and severityAlloimmune hemolysisCauses: “Major hemolytic” transfusion reaction

“Delayed hemolytic” transfusion reactionIV IgLiver transplant ― recipient has an RBC antigen the

allograft lacksSpherocytosis (+ agglutination), DAT+, antibody screen

or RBC eluate shows antigen specificityTreatment: Dependent on cause and severity

Anemias

Jehovah’s Witness

Determine which blood component(s) the patient will accept, including CellSaver blood

Be sure the patient understands the risks of refusing blood products

Ask the hardest question and document ― “If your life depended on a blood transfusion, would you prefer to die or to receive transfusion?”

Have the patient and spouse or next of kin (who may have minor dependents) release the physicians and hospital from responsibility for an adverse outcome due to refusal of blood products

Treatment options: Iron, erythropoietin, oxygen, non-blood product treatment of coagulopathy

Coagulopathies

Tests: Protime (INR), PTT, fibrinogen, D-dimers, occasionally factor level(s), ? bleeding time

Only a few causes of isolated prolonged PT:

Mild vitamin K deficiency or warfarin effect

Mild liver dysfunction

Mild DIC

Congenital factor VII deficiency (any severity)

Mild common coagulation pathway deficiencies (congenital deficiency of factor X, V, II, or fibrinogen)

Coagulopathies

Only a few causes of isolated prolonged PTT:

Mild liver dysfunction

UFH, LMWH, fondaparinux, bivalirudin

Congenital deficiency of VIII (including VWF), IX, XI, XII, prekallikrein, HMW kininogen)

Lupus anticoagulant (common)

Acquired factor VIII inhibitor (rare)

Coagulopathies

Clinical consequences depend on cause of prolonged PTT!

Cause PTT Consequence

Factor VIII inhibitor 50 sec Major spontaneousbleeding

Severe XII deficiency 120 sec Not a bleeding disorder

(factor XII 1%)

Mild von Willebrand disease 35 sec Surgical bleeding

(factor VIII and VWF 40%)

Lupus anticoagulant 45 sec Thrombotic tendency

Coagulopathies

Only a few causes of combined prolonged PT/PTT:

Dilutional coagulopathy (during exsanguination or plasmapheresis)

DIC / fibrinolysis

Severe liver dysfunction

Anticoagulants

Congenital deficiency (factor X, V, V/VIII, II, fibrinogen)

Acquired factor V inhibitor (topical bovine thrombin)

Acquired factor X deficiency (primary amyloidosis)

Coagulopathies

Only a few causes of hypofibrinogenemia:

Dilutional coagulopathy (exsanguination, plasmapheresis)

DIC / fibrinolysis

Severe liver dysfunction

Congenital

Coagulopathies

Bleeding disorders with normal PT, PTT, fibrinogen:

Thrombocytopenia and platelet dysfunction

von Willebrand disease (common)

mild hemophilia (VIII or IX) carrier state in women

factor XIII deficiency (very rare)

Available treatments for bleeding disordersFFP ― all clotting factorsCryoprecipitate ― fibrinogen, VWF, VIIIConcentrates ― VIII, VWF, IX (including “4-factor

concentrates”), XIIIRecombinant VIIa ― for factor VIII or IX inhibitors,

congenital factor VII deficiencyFEIBA (factor VIII inhibitor bypassing activity)Vitamin K ― to prevent/correct deficiency, reverse warfarinDDAVP (desmopressin) ― raises factor VIII/VWF levelsAminocaproic and tranexamic acid ― mild fibrinolytic

inhibitionHigh-dose conjugated estrogens ― multiple effectsProtamine sulfate ― reverses UFH well and LMWH

somewhatTPO receptor agonists ― may raise platelet count

Initial approach to the exsanguinating patient

Identify the site of bleeding, and target it for attention

Establish enough large-gauge venous accesses

Aggressive volume resuscitation to avoid shock state

Avoid pressors if possible

RBC transfusion

Blood products to avoid dilutional coagulopathy

FFP

cryoprecipitate

platelet transfusion

If bleeding is diffuse oozing and refractory, then consider some combination of a fibrinolytic inhibitor and high-dose conjugated estrogens

Indications/risks of transfusing blood productsRBC indications: “severe” or symptomatic anemia,

especially with ongoing bleeding or hemolysis

Platelet (single- or multiple-donor) indications:

<100,000 with serious active bleeding

<75,000 with upcoming invasive intervention

<20,000 with sepsis or other bleeding liabilities

<10,000

Volume overload

Alloimmunization; cross-matching difficulties and resulting delays

Hepatitis C and HIV, other infections

Allergic reactions

Thrombophilia testing

dRVVT ― anticoagulants may produce “borderline” results

Cardiolipin and beta2-glycoprotein I antibodies ― always valid

ATIII ― GAG anticoagulants and DIC consume it

PS ― half bound to C4bBP, an acute phase reactant; order total Ag, not activity

PS, PC, ATIII ― all reduced if liver dysfunction present

VIII ― an acute phase reactant

Factor V Leiden and prothrombin G20210A ― invalid in OLT and BMT pts; APCR (activated protein C resistance ratio) is valid, factor II (prothrombin) is valid if protime is normal

The anticoagulants

Glycosaminoglycans (GAGs) ― UFH, LMWH (e.g., enoxaparin), fondaparinux

Vitamin K antagonist ― warfarin

Parenteral anti-thrombins ― argatroban (Argatroban), bivalirudin (Angiomax)

Oral anti-thrombin ― dabigatran (Pradaxa)

Oral anti-Xa’s ― rivaroxaban (Xarelto), apixaban (Eliquis)

Glycosaminoglycan Anticoagulants

heparin (UFH) LMWH Fondaparinux

Source Porcine/bovine Altered UFH Synthetic

Mean # saccharides 36 13 5

Action ATIII, IIa>Xa ATIII, Xa>IIa ATIII, Xa

Plasma protein binding +++ + +

Bioavailability Variable 90% 100%

Half-life, hr Variable, ~6 (SQ) ~6 (SQ) ~17 (SQ)

<1-3 (IV)

PF4 binding ++ ++ ++

GAG/PF4 antibodies ++ ++ ++

HIT 1%-3% 0.3%-0.8% Almost never

Effect of renal dysfunction ++ ++ ++

Monitoring PTT Anti-Xa Anti-Xa

Protamine as antidote ++ + –

Pregnancy category C B B

Heparin-induced thrombocytopenia

HIT remains primarily a clinical diagnosis!Platelet count falls between d. 4-14 of de novo therapy

by 50% of greaterConsider other causes of thrombocytopeniaHeparin-PF4 EIA usually strongly positive, almost never

negative, IgG-only assays improve specificity; SRA more specific but time-consuming, expensive

Thrombosis (anywhere) occurs in about 30% of cases, may be multifocal, often devastating, often litigates

Platelet count usually recovers quicklyPatients remain hypercoagulable for about 2 wksArgatroban dosage is reduced for hepatic insufficiencyBivalirudin dosage is reduced for renal insufficiency

The newer anticoagulants

Acute AF Ortho VTE

HIT VTE proph proph proph ACS

Argatroban *

Bivalirudin * *

Dabigatran * * *

Rivaroxaban * * * *

Apixaban * * *

* = FDA approved indication

* = non-FDA approved indication

GAGs and VKAs — Still Important

Cardiopulmonary bypass: UFHProsthetic heart valves: VKAChronic valvular AF: VKAChronic non-valvular AF: VKA still acceptable if TTR very

good and/or patient can’t afford a new anticoagulantHypercoagulability of malignancy: GAGsAntiphospholipid syndrome: VKANon-orthopedic med/surg VTE prophylaxis: GAGs or VKAPregnancy: GAGsBreast feeding: GAGs or VKAAdvanced renal failure: UFH, VKAMorbid obesity: GAGs, VKA