Ebook Irwin & rippe''s manual of intensive care medicine (6/E): Part 2

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88 D isord e rs of H e m ostasis

Ada m C u ke r a n d S u m a n L Sood

I THE BLEE D I N G PATIENT: G E N ERAL PRINCI PLES

A Etiology

1 Bleeding disorders (Table 88- 1 ) may be secondary to the following:

a Defects in the activity of platelets

b Defects in the activity of one or more coagulation factors (coagulopathy)

c Congenital causes

d Acquired causes

2 Hematology consultation is often necessary if the cause of bleeding

is not immediately apparent and/or if specialized laboratory testing is required for diagnosis

B Diagnosis

1 Clinical presentation

a Identify the site of bleeding

i Platelet disorders tend to cause mucocutaneous bleeding (e.g., epistaxis, oral, gastrointestinal [GI] , genitourinary, ecchymosis)

ii Coagulopathies (i.e., deficiencies in the activity of coagulation factors) tend to cause deep soft tissue bleeding (e.g., into joints and muscles)

iii Bleeding from a single site (e.g., a surgical site, GI tract) warrants evaluation for an anatomic cause of bleeding

6 3 7

Hemoph i l ia A Hemoph i l ia B othe r factor d eficiencies

Acq u i red

M ed ications Renal d isease Myelodysplasia Myeloprol iferative

d isorders Vita m i n K d eficiency Liver d i sease Exposu re to

a nticoagula nts

D I C Tra u ma Acq u i red factor

i n h i bitors

'For defects i n platelet function due to th rom bocytopen i a , see Chapter 89

'Deficiency of van Willebra nd factor leads to red uced binding of platelets to sites of vascular

i nj u ry a n d to one a n other

DIC, d isse m i n ated i ntravasc u l a r coagulation

b Obtain the personal and family bleeding history

i Congenital disorders: life-long history of bleeding, posmve family history Exceptions are possible (e.g., mild hemophilia)

ii Acquired disorders: often no previous history of bleeding, no family history

c Perform a careful physical examination

i Skin: ecchymosis, petechiae, or nonpalpable purpura

ii Hemarthrosis: warm, swollen joints

iii Mucosa! surface abnormalities (e.g., nasal or oral pharyngeal mucosa)

2 Perform tiered laboratory evaluation

(a) Prolonged PT may indicate defect in tissue injury (also known as extrinsic) pathway of coagulation

(b) Prolonged aPTT may indicate defect in contact (also known

as intrinsic) pathway of coagulation

(c) Prolonged PT and aPTT may indicate single defect in com­mon pathway of coagulation or multiple defects

Tissue inj u ry pathway Contact pathway

1 1 - Thrombin !

Fibrin clot Figure 88- 1 The coagulation cascade may not fully represent the process of coagulation in vivo, where activation of coagulation usually is initiated through the tissue injury (also known

as extrinsic) pathway of coagulation, which subsequently can activate the contact (also known as intrinsic) pathway through thrombin-mediated activation of factors VIII and XI (not shown) The tissue injury system involves binding of activated factor VII to tissue factor and activa­tion of factor X, whereas the contact system involves activation of factor XI by contact factors such as factor XII and subsequent activation of factor IX, which in conjunction with activated factor VIII subsequently activates factor X The common pathway involves the activated fac­tor X-mediated cleavage of factor II to yield rhrombin, which cleaves fibrinogen to form fibrin clot The fibrin clot is strengthened through the cross-linking action of factor XIII (not shown) aPTT, activated partial thromboplastin time; PT, prothrombin time

TA B L E 8 8 - 2 Selected Causes o f a Prolonged Activated Partial

Thromboplastin Ti me (aPTT) and/or Prothrombin Ti me (PT)' Isolated prolonged aPTT Isolated prolonged PT Prolonged a PTT and PT

v o n Wil lebra n d d i seasec

Wa rfa rin exposu re Vita m i n K d eficiency Liver synthetic dysfu nction Congenita l d eficiency

of factor VI I

M i ld D I C

D I C Liver synthetic dysfu nction

S u prathera pe utic wa rfa r i n

or h e p a r i n Exposu re t o d i rect thro m b i n i n h i b itors (a rgatroba n , d a b igatra n ) Congentia l d eficiency of factors 1 1 , V, or X Hypo- or dysfi brinogenemia

Su perwa rfa rin exposu red Vita m i n K d eficiency Exposu re to FXa i n h i b itors ( riva roxa ba n , a pixa ba n ) e

'B leed ing d isorders that typically do not featu re a prolongation i n t h e a PTT or P T include, but a re not l i m ited to, platelet fu nction d isorders, von Wil lebrand d isease, FXl l l deficiency, antiplasm i n or plasminogen activator i n h i btor- 1 deficiency, and d isorders of the vascu lature or

i ntegu ment (e.g., Ehlers-Da n los, Osler-We ber-Rend u , scu rvy)

bNot associated with bleed ing

'VWD (especially type 1 ) a lso may featu re a norm a l a PTT

"Su perwarfa rin pesticides include brod ifaco u m , bromod iolone, cou mafuryl, and d ifenaco u m DIC, d isse m i n ated i ntravasc u l a r coagu lation; H M WK, h igh molec u l a r weight kini noge n

' M a y not prolong P T a n d APTT

6 4 0 I SECT I O N 9 • H E M A T O L O G I C P R O B L E M S I N T H E I C U

b Specialized testing

i Mixing study ( 1 : 1 mix of patient and normal plasma) to detect when an inhibitior may be present

(a) Indication: prolonged PT or aPTT

(b) If prolongation completely corrects with mixing -7 suggests factor deficiency

(c) If prolongation does not completely correct with mixing -7

suggests that an inhibitor is present (either specific to an individual coagulation factor or nonspecific, such as a lupus anticoagulant)

ii Measurement of individual coagulation factor levels

(a) aPTT prolongation: request factors VIII, IX, and XI (b) PT prolongation: request factors II, V, VII, X, and fibrino-gen

(c) von Willebrand factor (VWF) levels

(d) Platelet function studies

(e) FXIII levels

I I ACQU IRED DISORDERS OF H E M OSTAS IS

A Antithrombotic therapy induced

1 General Principles

a The medication administration history can suggest bleeding due to anticoagulant and antiplatelet agents that is common in the ICU See chapter 90 on Antithrombotic therapy in critically ill patients

B Vitamin K deficiency

1 Pathophysiology

a Inadequate dietary intake of vitamin K

b Malabsorption of fat-soluble dietary vitamin K

c Decreased production of vitamin K by intestinal flora (which may be destroyed by antibiotics)

2 Diagnosis

a Prolonged PT (corrects with mixing)

b Decreased levels of vitamin K-dependent clotting factors (II, VII, IX, and X)

3 Treatment

a Phytonadione (vitamin K1) administration

b May be given PO or IV at a dose of 1 to IO mg/day

i IV dosing associated with small risk of anaphylaxis

(a) Administer over 30 minutes with close monitoring (b) Smaller doses (e.g., 1 mg) advised

ii SC dosing is discouraged due to erratic absorption

c Treatment may be given empirically without confirmatory laboratory studies

i PT should begin to normalize within several hours of IV admin­istration of vitamin K1 •

C Coagulopathy of liver disease

1 Pathophysiology

Chapter 88 • D i sorders of Hemostas is I 6 4 1

a Deficiency of hepatically synthesized clotting factors including the vitamin K-dependent factors (II, VII, IX, and X) and factors V, XI, XII, and fibrinogen

b Owing to any cause of liver disease that impairs synthetic function

2 Diagnosis

a Prolonged PT ± prolonged aPTT

b Decreased levels of fibrinogen, factors II, V, VII, IX, X, XI, and XII

i Factor VIII, which is not produced in hepatocytes, is typically normal or elevated

c Other laboratory evidence of liver disease (e.g., decreased albumin, elevated alanine aminotransferase/aspartate aminotransferase)

3 Treatment

a Blood products

i Should be administered only if bleeding, at high risk of bleeding,

or when an invasive procedure is planned

ii Isolated mildly-moderately prolonged clotting times without bleeding not sufficient grounds for treatment

iii Ongoing treatment may be required until liver synthetic defi­ciency is resolved (e.g., by definitive treatment, such as liver transplantation, or recovery following shock liver)

b Fresh frozen plasma (FFP)

i Usual dose: infusions of approximately 1 0 to 1 5 mL/kg (usually

3 to 5 250 mL units)

ii Severe hepatic failure and ongoing bleeding: consider continuous infusion (FFP drip)

iii Goal: cessation in bleeding

(a) A target INR of :::; i 5 is often cited but may be difficult to achieve

iv Be alert for signs of volume overload

2 Etiology

a Infection/sepsis

b Malignancy (e.g., acute promyelocytic leukemia, Trousseau syn­drome)

6 4 2 SECT I O N 9 • H E M A T O L O G I C P R O B L E M S I N T H E I C U

c Obstetrical complications (e.g., placental abruption; hemolysis, elevated liver enzymes, and low platelet count [HELLP] syndrome; amniotic fluid embolism)

d Tissue damage (e.g., trauma, burns)

e Vascular abnormalities (e.g , abdominal aortic aneurysm, giant hem­angioma)

f Toxic procoagulant molecules (e.g , snake bite)

g Fat embolism (e.g., fracture of long bones, sickle cell crisis)

3 Diagnosis

a Presence of an underlying etiology

b Laboratory testing

i Decreased fibrinogen (due to consumption)

ii PT/aPTT may be prolonged (due to consumption of clotting factors)

iii Thrombocyropenia may be present (due to accelerated platelet consumption)

iv Increased o-dimer, a measure of cross-linked fibrin degradation products (due to accelerated fibrin degradation)

v Red blood cell fragments (schisrocytes) may be present on blood smear

4 Treatment

a Treatment of the underlying cause (e.g., antibiotics for sepsis, delivery for pregnancy related)

b Hemostatic therapy (for dosing, see Table 88-3)

TA B L E 88-3 Management o f Disseminated l ntravascu lar Coagu lation

( D I C) : Blood Prod ucts•

Component Typical

dose

Assoc iated laboratory parameterb

P latelets 1 dosec Platelet cou nt

Cryoprec i pitate 1 0 u n its Fibrinogen

F F P 3-5 u n its a PTT/PT

Target laboratory para meter

No c l i n ically significant bleed ing

>10 K/µL

>80- 1 00 mg/d l

C l i n ica l ly sign ificant bleed ing

>20-50 K/µL

>80- 1 00 mg/d l ::; 1 5 x u p per

l i m it norma l reference

ra nge

'Tra nsfuse blood prod ucts o n ly if c l i n ica lly sign ifica nt bleed ing or h igh risk of bleed ing 'Before transfusion , esta blish baseline platelet count, PT, a PTT, a-d imer, and fibrinoge n Fol low laboratory para m eters every 4-6 h u ntil D I C resolves and u nderlying cond ition successfu lly treated

'O ne dose of platelets is equal to 1 u n it of si ngle-donor platelets or a fou r or six pack of pooled

ra ndom donor platelets

FFP, fresh frozen plasma; a PTT, activated pa rtial throm boplasti n time; PT, proth rom bin time

Chapter 88 • D i sorders of Hemostas is I 6 4 3

i Should be given only to patients with high risk for bleeding, with clinically significant bleeding, or in need of invasive procedures (a) Platelet transfusion

(b) Cryoprecipitate

(c) FFP

(d) Coagulation tests (PT, aPTT, fibrinogen, platelet count) should be monirored frequently to assess response to hemo­static therapy

ii For refractory bleeding (e.g., mucocutaneous oozing, ongoing bleeding from catheter exit sites) despite above measures, con­sider low-dose heparin

(a) Typical dose: 5 to 10 units/kg/h (no bolus)

(b) Avoid in intracranial/GI bleeding, placental abruption, and imminent surgery

E Trauma-induced coagulopathy

1 Pathophysiology

a Major contributor is massive volume resuscitation with fluids or packed red blood cells (PRBCs) , which are deficient in clotting factors and platelets, leading to dilutional thrombocytopenia and coagulopathy

b Other possible contributing factors

i Acidemia (impairs activity of clotting cascade)

ii Hypocalcemia (impairs activity of calcium-dependent clotting factors)

iii Hypothermia (impairs platelet function)

iv Concurrent DIC

a Liberal transfusion of platelets, FFP, and cryoprecipitate

i Goals: aPTT/PT :5 1 5 x upper limit of normal; fibrinogen 2: 1 00 mg/dL; platelets > 5 0,000/µL

b Body and fluid warming to treat hypothermia

c Correction of electrolyte and acid-base disturbances

d Consider tranexamic acid, recombinant factor VIia (rhFVIIa) , or prothrombin complex concentrate in otherwise uncontrolled bleed­ing (further studies warranted)

F Acquired hemophilia

1 Pathophysiology

a Neutralizing autoantibodies against endogenous coagulation factor VIII

a Prolonged aPTT (does not correct with mixing)

b Low or unmeasurable factor VIII activity level

c Inhibitor titer using the Bethesda assay; reported in Bethesda units (B.U.)

(b) rhFVIIa: 90 µg/kg IV every 2 hours initially

b Inhibitor eradication

TA B L E 88-4

i Prednisone (typically 1 mg/kg/day PO) initially

ii Cyclophosphamide (typically 2 mg/kg orally) or rituximab (typically 375 mg/m2 IV weekly x 4 weeks) is added if inhibitor persists after 3 weeks of prednisone

(a) Some experts advocate the initial concurrent use of predni­sone and cyclophosphamide or rituximab

(b) Third-line immunomodulatory agents: cyclosporine, azathio­prine, intravenous immune globulin (IVIG)

Bypassi ng Agents for the Treatment of B leed ing Due to an I n h i b itor

Bypassing agent

FEI BA

Description Activated proth rom b i n com plex concentrate ( plasma-derived)

G Renal failwe/wemic platelets

1 Pathophysiology

Chapter 88 • D i sorders of Hemostas is 6 4 5

a Uremic toxins impair platelet function in some patients with kidney disease

2 Diagnosis

a Abnormal platelet function testing (rarely necessary)

b Note: the degree of azotemia does not correlate well with the risk of bleeding

3 Treatment

a Desmopressin acetate (DDAVP) (for dosing, see Table 88-5)

b Correction of anemia: target hematocrit �30%

i May improve platelet function by facilitating interaction of plate­lets with the vessel wall

ii Accomplished acutely by red cell transfusion and chronically by administration of erythropoierin-srimularing agent

b Platelet function resting may be required to establish a qualitative defect, as distinguished from decreased plareler function due to rhrombocytopenia (as commonly occurs in MDS and spent-phase MPD)

3 Treatment

a Trear underlying disorder

b Consider platelet transfusions for clinically significant bleeding

I l l CONGEN ITAL DISORDERS OF H E MOSTAS IS

6 4 6 I SECT I O N 9 • H E M AT 0 L 0 G I C P R 0 B L E M S I N T H E I C U

lt;M!j:l:fj Treatment of von Wil lebrand Disease

D DAVP Releases 0.3 µg/kg i n 50 m l F l u i d restrict (::;;750

VWF a n d norma l sa l i n e m l i n t h e 24 FVl l l from ( N S ) IV• over 20 h after dosi ng) endoth e l i a l m i n ; may repeat and l i m it d oses cells i nto in 1 2-24 h, maxi- to red uce risk of

c i rc u lation m u m 2-3 doses hyponatre m i a

Tachyphylaxis occ u rs after 2-3

d oses

VWF-conta i n i ng D i rect replace- For major bleed ing Goal VWF a n d factor V I I I ment of or proced u res: FVl l l leve ls a re concentrate d eficient 40-80 RCoFb >80%-100% for

( H u mate-P, VWF a n d u n its/kg IV bol u s major bleed i ng Alpha nate, factor V I I I q l 2 h i n itially or proced u res

Wi late) activity fol lowed by 20-60 Trough levels

RCoF u n its/kg should be

q l 2 h once performed to hemostasis has e n s u re ade-

been esta bl ished q uate dosing e-a m i noca proic I n h i bits IV: 5 g ( i n 250 For VW D , adju nc-

fi brinolysis a maxi m u m of 5 treatment of

bleed i ng Avoid if active hematu ria ,

D I C

'I ntra nasal formu lation (Stimate) a lso ava i lable; dose for a d u lts weigh ing >50 k g is 1 50 µg (one spray) i n each nostri l

'RCoF, Ristocetin cofactor, a measure o f VWF activity

D DAVP, desmopressin acetate; VWF, von Willebra nd factor; RCoF, ristocetin cofactor; VWD, von Wil lebrand d isease; D I C , d isse m i nated i ntravascular coagu lation

TA B L E 8 8 - 6

Chapter 88 • D i sorders o f Hemostas is I 6 4 7

B leed ing Phenotypes i n Hemop h i l ia by Factor Level

Severity of hemop h i l ia Factor level Usual man ifestation of

bleed ing Severe

i Males only affected

S ponta neous; often m a n ifests i n

i nfa ncy/c h i l d hood

S ponta neous or tra u m a i n d uced Tra u m a i n d uced only

(a) Family history usually shows affected males, but some patients are affected by de novo mutations, leading to nega­tive family history

ii Females typically are asymptomatic carriers

(a) Owing to variable lyonization, some females are symptomatic earners

2 Clinical presentation

a Bleeding phenotype determined by the level of residual clotting factor activity (Table 88-6)

b Bleeding into soft tissues (joints and muscles) is most common

i Bleeding at any site, however, is possible

ii Bleeding may be life threatening or limb threatening (Table 88-7)

i Prolonged aPTT (corrects with mixing)

ii Reduced or unmeasurable activity level of factor VIII (hemo­philia A) or factor IX (hemophilia B)

Limb- or Life-Threatening B leed ing Syndromes in Hemoph i l ia

C l i n ica l presentation Head tra u m a , severe headache, menta l status cha nges

Diagnostic testing Stat head CT

Retroperitonea l

Retropharyngea l

N ew bac k pa i n Strid o r

Stat C T o f a bdomen/pelvis Late ra l x-ray of neck, ENT eva l uation

Com pa rtment

synd rome

Recent i ntra m uscular bleed ;

d isproportionate pa i n , neu rovascu l a r fi n d i ngs

Serial n e u rovasc u l a r exa m i nations, vasc u l a r

s u rgery eva l uati o n ,

u ltraso u n d , CT/M R I

CT, com puted tomogra phy; ENT, ear nose th roat; M R I , magnetic resonance i maging

6 4 8 I SECT I O N 9 • H E M A T O L O G I C P R O B L E M S I N T H E I C U

4 Treatment (Table 88-8)

a If clinical suspicion for limb- or life-threatening bleeding, administer factor before completing radiographic/diagnostic work-up

b Factor VIII and IX concentrates

i Contain much higher concentrations of factor than FFP or cryo­precipitate (use of both should be avoided if possible due to large volume required and lack of viral inactivation)

ii Both plasma-derived and recombinant products available iii Administered by IV push (Table 88-8)

c DDAVP (for dosing, see Table 88-5)

i Effective in some cases of mild hemophilia A only

d Antifibrinolytic agents: £-aminocaproic acid and tranexamic acid (for dosing, see Table 88-5)

i Useful for mucosa! bleeding or procedures involving mucosa

e Transfusion of PRBCs (if anemic)

5 Complications

a Inhibitor formation

i Alloantibody directed against deficient coagulation factor

ii Occurs in 25% of patients with severe hemophilia A; less com­mon in hemophilia B and mild/moderate hemophilia A lf.j;l!j:l:§:I Treatment of B leed ing i n Hemoph i l ia

Disorder Su btype Treatment for Treatment for

m i nor bleedi ng• major bleedi ngb Hemoph i l ia A M i ld D DAVPc or FVl l l FVl l l

i n itial lyd IV i n itia l ly•

Hemophilia B Any FIX concentrate, FIX concentrate,

50-60 u n its/ 1 00-120

kg IV i n itia l ly• u n its/kg IV

i n itia l ly•

•For exa m ple, typical hemarthrosis or i ntra m uscular hem orrhage, epistaxis

'For exa m ple, i ntracra n i a l , retroperitona l , or GI bleed ing

'For dose of D DAVP, see Ta ble 88-8

dMay repeat in 12 to 24 h if ongoing sym ptoms

Treatment periproced ura l ly

D DAVPc, or FVl l l concentrate,

50 u n its/kg

IV pre-op•

FVl l l concentrate,

50 u n its/kg IV pre-op• FIX concentrate,

1 00-1 20

u n its/kg IV

pre-o p•

'Fol low i n itial dose with 25 u n its/kg ( FVl l l concentrate) or 50 to 60 u n its/kg (FIX concentrate)

IV every 8 to 12 h to m a i nta i n factor activity <:50% for 3 to 10 d or as long as bleed ing is present Consider adj u nctive E-a m i nocaproic acid for m u cosa l bleed ing or proced u res i nvolvi ng mucosa Less-i nvasive proced u res (e.g , endoscopy with biopsy) may req u i re less i ntensive factor replacement

D DAVP, desmopressin acetate

Chapter 88 • D i sorders of Hemostas is I 6 4 9

iii Causes bleeding and poor response to infusion of factor concen­trate

b Blood-borne viral infection

i High rate of infection with human immunodeficiency virus (HIV) , hepatitis C virus (HCV) , and hepatitis B virus (HBV) acquired through tainted blood products in 1 970s and 1 980s

ii Currently available factor products in developed countries undergo viral inactivation that greatly reduces infection risk or are recombinant

c Hemophilic arthropathy

i Chronic joint damage due to recurrent hemarthroses

B von Willebrand disease (VWD)

1 Pathophysiology

a Deficiency or dysfunction of VWF

b Normal function of VWF

i Tethers platelets to the subendothelium

ii Bridges platelets and links them to the fibrin clot

iii Serves as a carrier for factor VIII, protecting it from accelerated clearance

i Usually measured by ristocetin cofactor assay

c Decreased factor VIII activity

i aPTT may be prolonged if factor VIII activity sufficiently decreased, but frequently is normal

d VWF multimer electrophoresis can help distinguish among types

5 Treatment (Table 88-5)

a DDAVP

i Synthetic analog of vasopressin

ii Primarily effective in type 1 VWD, some type 2 VWD (a) Patients should have previously undergone therapeutic challenge to assess responsiveness

6 5 0 I SECT I O N 9 • H E M AT 0 L 0 G I c p R 0 B L E M s I N T H E I c u

(b) If not previously performed or data unavailable, must mea­sure postinfusion VWF and factor VIII activities to ensure hemostatic levels, or administer VWF-containing factor VIII concentrate (see below) instead of DDAVP

iii May worsen thrombocytopenia in patients with type 2B VWD

b VWF-containing factor VIII concentrate

c Antifibrinolytic agents: £-aminocaproic acid and tranexamic acid

a DDAVP (for dosing, see Table 88-5)

b Antifibrinolytic agents: £-aminocaproic acid and tranexamic acid (for dosing, see Table 88-5)

a Mostly autosomal recessive inheritance

2 Incidence: very rare

Chapter 88 • D i sorders of Hemostas is I 6 5 1

b Deficiency of fibrinogen usually treated with cryoprecipitate or fibrinogen concentrate

c Deficiency of factor VII usually treated with rh VIIa

d Deficiency of factor XIII usually treated with cryoprecipitate of factor XIII concentrate

Fijnvandraat K, Cnossen MH, Leebeek FW, et al Diagnosis and management of haemophilia

BM] 201 2;344:e2707

A concise overview of hemophilia and its management acutely and in the outpatient setting

Galbusera M, Remuzzi G, Boccardo P Treatment of bleeding in dialysis patients Semin Dial 2009;22:279-286

A review of the pathophysiology and management of bleeding in patients with end-stage renal disease with a focus on uremic platelets

Kamal AH, Tefferi A, Pruthi RK How to interpret and pursue an abnormal prothrombin time, activated partial thromboplastin time, and bleeding time in adults Mayo Clin Proc 2007;82: 864-873

Practical guide for the evaluation of a patient with abnormal clotting times

Keeling D, Tait C, Makris M Guideline on the selection and use of therapeutic prod­ucts to treat haemophilia and other hereditary bleeding disorders Haemophilia 2008; 14(4) :67 1 -684

Evidence-based guidelines on the selection and use of therapeutic products to treat hemo­philia and other hereditary bleeding disorders

Levi M, Toh CH, Thachil J, et al Guidelines for the diagnosis and management of dissemi­nated intravascular coagulation British Committee for Standards in Haematology

Br j Haematol 2009; 145:24-33

Evidence-based consensus guidelines on the diagnosis and management of DIC

Murthi SB, Stansbury LG, Dutton RP, et al Transfusion medicine in trauma patients: an update Expert Rev Hematol 20 1 1 ;4:527-537

A review on blood product replacement in trauma patients

Nichols WL, Hultin MB, James AH, et al von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA) Haemophilia 2008; 14: 1 7 1 -232

A thorough overview of and evidence-based guidelines for the diagnosis and treatment of von Willebrand disease Also see the more detailed document online at http://www nhlbi nih.govlguidelines/vwdlindex.htm

Nurden AT, Freson K, Seligsohn U Inherited platelet disorders Haemophilia 20 1 2; 1 8 (Suppl 4) : 1 54-1 60

Description of congenital platelet disorders, including qualitative platelet defects, and options for therapy in the setting of acute bleeding

Th ro m b o cyto p e n i a

i n the C riti ca l Ca re Pati e nt

2 Increased destruction, consumption

3 Increased sequestration in enlarged spleen

4 Dilutional-effect of massive transfusion and fluid resuscitation

5 States with multiple causes of thrombocytopenia

a Cirrhosis with portal hypertension

b Hepatitis

c Human immunodeficiency virus (HIV)

d Other viral illnesses

e Patients with multiple medical problems on multiple drugs

C Diagnosis

1 Complete blood count with peripheral smear examination

a Rule out pseudothrombocytopenia due to platelet clumping

b Review for erythrocyte abnormalities: schistocytes, teardrops, nucle­ated red blood cells

c Review for white blood cell abnormalities: immature or dysplastic forms

2 Coagulation testing

a Identify associated coagulation abnormalities

3 Additional blood tests

a Viral titers and antibody (e.g., HIV, hepatitis C [HCV] infection)

b Autoimmune disorders-antibody testing

c Other-see specific disorders

4 Radiologic

a Abdominal ultrasound-evaluation of spleen size

b CT scanning-evaluation for lymphoproliferative disease

6 5 3

I n sertion of centra l venous cathetersb

Ad m i n istration of thera peutic a nticoagu lation Secondary prevention of serious bleed ing (e.g , gastroi ntesti n a l ) d u e to severe throm bocytopen ia

M i nor s u rgery a n d some invasive proced u resc

M ajor su rgery Secondary prevention of i ntracra n ia l hemorrhage,

m icrovasc u l a r bleed i ng

'The va lues provided a re suggestions on ly; management m ust be i ndividualized with respect to the underlying cause of throm bocytopenia, presence of bleed ing, and other relevant clin ical factors 'Nontun neled catheters may be inserted with platelet counts in the lower end of the specified ra nge 'Representative proced u res include need le biopsies and endoscopy with biopsy; skin biopsy and bone ma rrow biopsy typica l ly may be performed at lower platelet cou nts than the specified range

5 Bone marrow examination indications

a Unclear pathophysiology

b Multiple cytopenias

c Suspected infiltrative process

D Therapy (Table 89-1)

1 Indications for platelet transfusion

a Bleeding or necessary invasive procedures

b Prophylactic-very severe (d 0,000/µL) thrombocytopenia or

<20,000 when fever or mucositis are present

c Other blood components as indicated to correct coagulation abnor­malities or severe anemia

d Relative contraindications to platelet transfusion

i Thrombotic thrombocytopenic purpura (TTP) unless bleeding is present-worsened thrombotic tendency reported

ii Immune thrombocytopenia unless bleeding present-poor or short-lived response

iii Heparin-induced thrombocytopenia (HIT) without bleeding­unknown

2 Nonspecific therapy for bleeding

a Antifibrinolytic agents-Epsilon-aminocaproic acid, tranexamic acid

b Recombinant factor VIia (Novo Seven)-unproven and controver­sial May be indicated in acute intracranial, other life-threatening bleeding in patients without response to platelet transfusion

3 Secondary thrombocytopenias-direct therapy at underlying cause(s)

4 Primary thrombocytopenia-depends on specific disorder

Chapter 89 • Throm bocytope n i a i n the Critical Care Patient 6 5 5

I I DECREAS E D PLATELET PRODUCTION

A Isolated thrombocytopenia

1 Drugs, ETOH, viral (e.g , HIV, HCV)

2 Decreased thrombopoietin-liver disease

3 Amegakaryocytic thrombocyropenia

B Mulriple cyropenias

1 Marrow roxins

a Drugs, alcohol, radiation

2 Nutritional-for example, B12 and/or folate deficiency

3 Metabolic-for example, thyroid disorders

4 Primary marrow disorders

5 Hemaropoietic stem cell disorders

a Marrow infilrration

6 Hemophagocyric syndrome

C Diagnosis

1 Peripheral blood smear

a Bizarre forms-for example, abnormal granulation suggests myelo­dysplasia

b Red blood cell abnormalities

i Teardrops, nucleated red blood cells-suggest marrow infiltrative diseases

ii Macrocyrosis-B 12 or folate deficiency, myelodysplasia

c White blood cell abnormalities

i Immature forms-suggest leukemia

ii Mulrilobed neutrophils, bizarre forms-B12 or folate deficiency, myelodysplasia

D Therapy

1 Direct at underlying or associated disorder

I l l I N C REAS E D SPLE N I C SEQUESTRATION

6 5 6 I SECT I O N 9 • H E M AT 0 L 0 G I c p R 0 B L E M s I N T H E I c u

IV DISORDERS OF I N C REAS E D PLATELET DESTRUCTION

A Characterized b y shortened platelet life span (normal 7 t o 1 0 days)

B Nonimmune-isolated or combined platelet consumption

b Associated with malignancy (e.g., lymphoproliferative disease)

c Complication of infection with HIV, HCV, hepatitis B virus (HBV) , Epstein-Barr virus (EBY) , Cytomegalovirus (CMV) , and others

d Drug associated

A General principles

1 Acure ITP may present with any severity of thrombocyropenia

2 Initial presentation frequently abrupt in onset

3 Petechiae, bruising, mucosal bleeding-most common manifestations

B Epidemiology

1 Adults-85% chronic relapsing disorder

2 Children-90% acute, self-resolving disorder

3 Female predominance (F:M = 3:2) except in children, elderly

C Etiology

1 Idiopathic, may present following acute viral illness

2 Secondary ITP may be initial presentation of connective tissue disease, lymphoproliferative malignancy, HIV infection

3 May be associated with antiphospholipid antibody syndrome

D Pathophysiology

1 Antibody against glycoproteins on the platelet membrane

2 Reticuloendothelial, especially splenic, platelet clearance

3 Inadequate platelet production response

4 Direct T-cell toxicity may play a part

Chapter 89 • Throm bocytope n i a i n the Critical Care Patient I 6 5 7

b Rule out associated disorders when indicated by history or clinical presentation

c Antiplatelet antibodies generally not helpful in diagnosis

d Bone marrow examination not required unless diagnosis uncertain or patient older than 60 years

i Normal-to-increased numbers of megakaryocytes without other abnormalities

F Treatment

1 Acute

a Corticosteroids

i Usual prednisone dose 1 to 2 mg/kg

ii Acute emergency-up to 1 g methylprednisolone IV

b lmmunoglobulin therapy-usually rapid response

i 1 to 2 g/kg IV administered over 2 to 5 days

ii Antifibrinolytic agents

(a) Epsilon-aminocaproic acid starting dose 1 to 2 g PO/IV q6 h Increase as needed up to 24 g total daily dose

(b) Tranexamic acid starting dose 500 mg to 1 g IV/PO q8 h (c) Contraindication-urinary tract bleeding, DIC

2 Chronic

Options for patients who relapse after immunoglobulin therapy or prednisone taper include splenectomy, thrombopoietin-mimetic agents, pulse corticosteroids, alkylating agents, monoclonal antibody, azathio­prine, and other immunosuppressive agents

G Complications

1 Therapeutic complications may interfere more with quality oflife and be more severe than bleeding risk in mild or moderately thrombocytopenic patients (30 to 100,000/µL)

2 Chronic steroid therapy and immunosuppression-severe osteoporosis, infections, and other complications

H Prognosis

1 Severe refractory ITP: 10% to 25% risk of significant bleeding during disease course

6 5 8 I SECT I O N 9 • H E M AT 0 L 0 G I c p R 0 B L E M s I N T H E I c u

V I I DRUG-ASSOC IATED AUTO I M M U N E THROMBOCYTO P E N IA

A General principles

1 Multiple drugs implicated

2 Most common offenders: quinine and derivatives, antibiotics, thiazide diuretics, IIb/IIIa inhibitors

3 HIT: treated differently; see below

B Diagnosis

1 History of exposure to possibly offending drug

2 Laboratory testing

a Drug-dependent platelet auroantibody-limited availability

b No other blood or hemostatic abnormalities identified

3 Contraindicated: readministration of suspected drug as diagnostic challenged

C Therapy

1 Discontinue suspected offending agent(s)

2 Intravenous gamma-globulin therapy: administer as for ITP

3 Platelet transfusion may be indicated for bleeding

4 Plasma exchange in severe refractory cases

V I I I H IT

A General principles

1 Immune reaction to a heparin/Platelet Factor 4 (PF4) complex

2 May be associated with life-threatening prothrombotic state

3 Discontinue all heparin therapy (including low molecular weight heparin [LMWH] and heparin flushes) while considering the diagnosis

4 Ultimately a clinical diagnosis

B Pathophysiology

1 Heparin bound to PF4 immunogenic

2 Antibodies bound to the heparin/PF4 complex cause platelet activation, aggregation, and thrombin generation

3 Thrombin further activates platelets

4 Large and small venous and arterial vessel thrombosis may occur

C Diagnosis

1 Clinical

a Exposure to any type, administration route, or dose of heparin

i Unfractionated > low molecular weight

ii Intravenous > subcutaneous

b Onset usually 4 to 10 days after initial heparin exposure

c >50% fall in platelet count more important than absolute

thrombo-cytopenia

d Post-op inflammatory state may mask a relative drop in platelet count

e Suspect if new or extension of thrombus during heparin anticoagulation

f 4T Score (http://www.qxmd.com/calculate-online/hematology/ hit-heparin-induced-thrombocyropenia-probability): estimates clinical probability of HIT

Chapter 89 • Throm bocytope n i a i n the Critical Care Patient I 6 5 9

(b) �2.00 OD units: approximately 90% risk of HIT

b Serotonin release assay (more specific; best combined with results of immunologic assay such as PF4 ELISA; specialized laboratories only)

c Heparin-platelet aggregation studies (specialized laboratories only)

D Treatment

1 Discontinue all heparin exposure

2 Rule out thrombosis-Doppler studies

3 Anticoagulation with alternative anticoagulants

a Direct thrombin inhibitors

i No antidotes

ii IV argatroban (direct thrombin inhibitor)-hepatic clearance iii IV bivalirudin (direct thrombin inhibitor)-increased half-life with renal insufficiency

b SC fondaparinux (synthetic pentasaccharide)-long half-life ( 1 7 hours), not reversible; use as initial treatment controversial

c Do not start Coumadin until platelet count recovery; overlap with a direct thrombin inhibitor (DTI)

E Prognosis

1 Associated with up to a 50% thrombosis rate, leading to serious morbidity and mortality without direct thrombin inhibitor therapy

2 Appropriate length of ongoing anticoagulation unclear, usually �30 days

IX ALLO I M M U N E THROMBOCYTOPEN IAS

2 Typically occurs 5 to 10 days posttransfusion of cellular blood component

3 Most common in multiparous women

B Pathophysiology

1 Alloimmunization to foreign platelet antigen occurs through pregnancy

or transfusion

2 Allogeneic platelet destruction with recall of antibody

3 Mechanism of associated autologous platelet destruction poorly understood

1 IV lmmunoglobulin 1 to 2 g/kg over 2 to 5 days

2 Plasma exchange in refractory cases

3 Poor responses to platelet transfusion

XI N O N I M M U N E THROMBOCYTOPENIA

A Combined consumption (DIC)

1 Associated with fibrinogen deposition and consumption

2 Sepsis, malignancy, obstetric complications, massive tissue injury, or snake bite

B Diagnosis

1 Peripheral blood smear

a Bands, toxic granulations, Dahle bodies

b May see red cell fragmentation (schistocytes)

2 Abnormal coagulation tests

a Increased prothrombin time (PT), partial thromboplastin time (PTT), or thrombin time

b Falling fibrinogen levels

c Increased o-dimer levels

C Treatment

1 Directed at the underlying cause

2 Support with transfusion therapy for bleeding

X I I ISOLATE D PLATELET CONS U M PTION

A Vascular injury, high shear flow-vasculitis, intravascular prosthetic devices

B Microangiopathic hemolysis-for example, TTP, hemolytic uremic syn­drome (HUS)

X I I I M I CROAN G I O PATH I C H E M O LYTI C ANEM IAS

A General principles

1 Isolated platelet consumption associated with intravascular hemolysis

2 Patients present with end-organ signs and symptoms due to microvascular thrombosis

B Etiology

1 Thrombotic thrombocytopenic purpura

2 Hemolytic uremic syndrome

3 Escherichia coli 0 1 57:H7 or Shigella species infection

4 Malignant arterial hypertension

5 Drug induced-for example, cyclosporine, mitomycin C, pentostatin, others

Chapter 89 • Throm bocytope n i a i n the Critical Care Patient 6 6 1

1 Peripheral blood smear-red cell fragmentation (schistocytes)

2 Elevated parameters of intravascular hemolysis-lactate dehydrogenase (LDH), indirect bilirubin

3 Normal coagulation tests

D Treatment

1 Discontinue offending agents

2 Treat underlying disorder

a Pregnancy associated-requires emergency delivery

3 HUS, TTP: see Sections XIV and XV

XIV THROM BOTIC THROM BOCYTO PENIC PURPURA

A General principles

1 Acute presentation of severe-to-moderate thrombocytopenia

2 Usually presents with fever, neurologic signs or symptoms, and/or renal abnormalities

3 Complete pentad of signs/symptoms (i.e., microangiopathic hemolysis, thrombocytopenia, fever, neurologic and renal abnormalities) is present

in fewer than 25% of cases

a Autoimmune: Autoantibody forms against ADAMTS- 1 3

b Congenital TTP: Familial decrease i n production o f functional ADAMTS- 1 3

2 Formation o f platelet thrombi i n microvasculature leads t o tissue ischemia and end-organ disease

3 Intravascular hemolysis by increased shearing forces

D Diagnosis

1 Laboratory

a Thrombocytopenia

b Schistocytes on peripheral blood film

c Elevated LDH and indirect bilirubin

6 6 2 SECT I O N 9 • H E M AT 0 L 0 G I C P R 0 B L E M S I N T H E I C U

d Hemostasis parameters otherwise normal

e Creatinine may be increased; hematuria may be present

f Usefulness of ADAMTS- 1 3 level and antibody for diagnosis 1s unclear

E Treatment

1 Medical emergency; >90% mortality rate without treatment

2 Institute immediate plasma exchange; replacement fluid must be plasma

a Continue daily until LDH and platelet count have normalized for 2

to 3 days

b Some centers taper frequency before stopping

3 Infuse plasma (4 to 6 units in adult) if plasma exchange delayed

a Primarily supportive (e.g., dialysis)

b Plasma exchange of value in some patients

c Majority of cases resolve with supportive care

2 Atypical cases: may resolve following inhibition of C5 (e.g., eculizumab)

S U G G E S T E D R E A D I N G S

Aster RH, Bougie DW Drug-induced immune thrombocytopenia N Eng] Med 2007;357: 580-587

Review of drug-related thrombocytopenias and approach to their management

Cines DB, Busse! JB, Liebman HA, et al The ITP syndrome: pathogenic and clinical diversity Blood 2009; 1 1 3 :65 1 1-652 1

Excellent review of secondary immune thrombocytopenias

Dragon-Durey MA, Blanc C, Garnier A, et al Anti-factor H autoantibody-associated hemolytic uremic syndrome: review of literature of the autoimmune form of HUS Semin Thromb Hemost 2010;36:633-640

Review of atypical HUS

Kitchens CS Thrombocytopenia and thrombosis in disseminated intravascular coagulation (DIC) Hematology Am Soc Hematol Educ Prog 2009;240-246

Chapter 89 • Throm bocytope n i a i n the Critical Care Patient 6 6 3

Review of clinical and laboratory findings and stratification of thrombotic and hemorrhagic risks

Linkins L-A, Dans AL, Moores LK, et al Treatment and prevention of heparin-induced thrombocycopenia: antithrombotic therapy and prevention of thrombosis, 9th ed American College of Chest Physicians Evidence-based Clinical Practice Guidelines Chest 20 1 2; 1 4 l (Suppl 2):e495S-e530S

Excellent review of the clinical presentation, pathogenesis, and expert guidelines for the diagnosis and management of HIT

Provan D, Stasi R, Newland AC, et al International consensus report on the investigation and management of primary immune thrombocyropenia Blood 20 1 0; 1 1 5 : 1 68-1 86 Immune thrombocytopenic purpura diagnosis and management guidelines by a panel of international experts

Tsai HM, Lian EC Antibodies co von Willebrand Factor-cleaving protease in acute thrombotic thrombocyropenic purpura N Engl] Med 1 998;339 : 1 5 85- 1 5 94

The classic paper describing the relationship of ADAMTS-13 and TTP

Tsai HM Autoimmune thrombotic microangiopathy: advances in pathogenesis, diagnosis, and management Semin Thromb Hemost 201 2;38(5) :469 482

Discussion of the advances that have been made in our understanding of the pathophysi­ology of the thrombotic microangiopathies and how these differences aid in differential diagnosis and treatment decisions

Warkentin TE, Smith JW The Alloimmune thrombocycopenia syndromes Transfus Med Rev

1 997; 1 1 :296-307

Review of platelet alloantigen systems and related immune thrombocytopenias

a Inhibits prostaglandin synthesis

B P2Y12 inhibitors (Table 90-2)

1 General principles

a Prodrugs requiring hepatic activation

b Antiplatelet effect can last for life span of platelet (7 to 1 0 days)

b Duration of effect is agent specific and is influenced by its binding (i.e., abciximab irreversible up to 1 0 days) and renal function/elimi­nation (i.e., for tirofiban and eptifibatide, 2 to 4 hours)

Aspi rin and Aspi ri n-Conta i n i ng Products

Drug I n d ications Dosi ng, timi ng, d u ration Mon itoring Preca utions and contraind ications Acetylsa l icyl ic Treatment of ACS +/- PCI Load ing dose: • C B C Precautions

(Aspirin) 8 1 mg if on prior a nti platelet bleed i ng • B leed i ng d i so rders

thera py • B lood • A lcohol use (th ree or more d ri n ks

8 1-325 mg/d ora l ly • LFTs • P regna ncy (th ird tri mester) Primary and secondary 8 1 -325 mg/d o ra l ly • Renal • GI d isorders

Acute thro m botic stroke 1 60-325 mg/d, in itiated withi n 48 h (in patients who a re not Contraindications

• H ypersensitivity to sal icylates

ca nd idates for thrombolyt- • C h i l d ren a nd teenagers with

ics and a re not receivi ng chic ken pox or fl u sym ptoms

system ic anticoagu lation)

(risk of Reye synd rome) Secondary prevention 75-325 mg/d sta rti ng 6 h

i n CABG, ca rotid fo l lowi ng p roced u re;

endarte rectomy patients if bleed i ng preve nts

ad m i n istratio n at 6 h afte r CAB G , i n itiate as soo n as

::r (1)

"D

� iii"

" u;-

en

•if.!.1:111::S:I•J!!f'.ll P2Y12 I n h i bitors "'

-Drug I nd ications Dosing, t i m i ng, d u ration Mon itoring Precautions and contra i n d i cations (/J

rn

( Plav ix) ACS +/- PCI PCI LD: 300-600 mg X l • C B C with d ifferential • I nterru ption o f clopidogrel m a y ca use 6

z

M a i nten a nce: 75 mg o ra l ly • B leed i ng time in-stent throm bosis with su bseq uent <D

Primary and secondary 75 mg o ra l ly once d a i ly • Lipid panel • I ndwe l l i ng epid u ra l cathete r rn prevention of M I i n (ticlopidi ne) • Com bi nation of aspirin and clopidogrel ;;::

Peri ph eral a rteri a l aggregometry a nd/ • Recent tra u m a , su rgery/bio psy, or "D

sti m u lated • Co nco m ita nt u se with potent CYP3A 0

( Effie nt) PCI M a i nten a nce: 10 mg/d phosphoprote i n i nd uce rs a nd i n h i bito rs (ticagre lor) r

ora l ly, consider 5 mg [VAS PJ • Use of d a i ly mai nte na nce doses ;;:: ora l ly once d a i ly i n phosph orylation) of aspiri n a bove 100 mg not (/J patients weigh i ng <60 kg • CYP2C l9 genotyp- reco m men ded (ticagre lor) z

ing if suspicion of • U nderlyi ng hemato logic d isorders -j

( B ri l i nta) PCI M a i ntenance: 90 mg twice (c lopidogrel) or platelet cou nt < 80,000/mm3

c

• Elevated triglycerides (ticlopidi ne)

• Clopidogre l concentrations may be red uced i n poo r meta bol izers of CYP2C l9

•1�1:1•=-:I•B'• P2Y12 I n h i bitors (continued)

• Recent stroke or T I A ( p rasugrel)

• Severe active bleed i n g (suc h

a s peptic u lcer o r i ntrac ra n i a l hemorrhage)

• Ne utro pen ia/th ro m bocytopen ia

• Severe l iver i m pa i rment

ACS, acute coronary synd romes; LD, loading dose; P C I , percuta neous coronary i ntervention; CBC, complete blood cou nt; LFT, l ive r function tests; M l , myoca rd ial

i nfarction; UA, unsta ble a ngina; TIA, tra nsient ischemic attack; A N C , a bsol ute neutroph i l count

"D

� iii"

" u;-

en

•t!1:11•::a:t•s• Glycoprotei n llB/11 IA I nh i b itors

IV i nfusion for 1 2 h in combination with fibri nolytic treatment or after

PC I , u n less com plications LD: 180 µg!kg IV bo l u s based on ABW ( maxi m u m 22.6 mg) as soon as possible, fol l owed by

2 µg/kg ABW/m i n (maxi m u m

1 5 mg/h ) i nfusion u nti l d isc harge

or CABG s u rge ry, u p to 72 h

If undergoing PCI , ad m i n ister a second 180 µg/kg IV bolus 10 m i n after t h e first and conti nue the infusion up to d ischarge, or for u p

t o 18-24 h after proced u re, which­

ever comes fi rst, a l lowi ng for up to

96 h of thera py Renal i m pa i rment:

CrCI <50 m Um i n ute, 1 80 µg/kg actua l body weight ( maxi m u m 22.6 m g ) IV bo l u s a s soo n as possible, fol l owed by 1 µg/kg/m i n (maxi m u m 7 5 mg/h ) i nfusion

Mon itoring

• Signs of bleed ing

• CBC

• a PTT wh i le

on heparin

• ACT d u ri ng PCI and prior

to sheath remova l

• Seru m

c reati n i ne

Precautions and contra i n d ications Precautions

• I ndwel l i n g epid u ra l cath eter

• Do not re move a rterial sheath u n l ess

a PTT is <45 s or ACT < 1 50 s a n d heparin

d iscontin ued for 3-4 h

• Platelet count below 1 50,000/mm3

• Renal insufficiency (eptifi batide a n d ti rofi ba n)

• Read m i nistration of a bcixi m a b may res u lt

i n hypersensitivity, throm bocytopenia, or

d i m i n ished benefit d u e to formation of h u man

a ntic h i m eric a nt i bod ies

• Hemorrhagic retinopathy Contraindications

• Active i nte rnal bleed i ng

• Abnormal bleed i ng with i n the p revious

30 d o r a h istory of b leed i ng d iathesis

• Concom itant or plan ned administration of other parentera l glycoprotein I l b/I l la inhi bitors

• Hyperse nsitivity to active ingred ient or a ny other p rod uct com ponent

• Hypersensitivity to m u rine proteins (a bcixi mab)

• Major su rgery (wit h i n the p revious 6 wk)

• Stro ke (with i n previous 30 d)

• Seve re hyperte nsion (systo lic p ress ure over

1 80 200 mm Hg or d iastol ic pressu re a bove

1 1 0 m m Hg)

"'

00

(/J c::j

r

0 -

rn

Cl

•t!l:i•=-:I•Sll Glycoprote i n llB/11 IA I nh i b itors (continued)

Drug

1irofi ban

(Aggrastat)

I nd i cations Dosi ng, t i m i ng, d u ration Mon itoring

ACS treat- LD: 0.4 µg/kg/m i n I V bo l u s for ment 30 min then 0.1 µg/kg/m i n for

1 2-24 h after PCI Renal i m pa i rment:

CrCI < 30 m l/m i n ute: Load 0.2 µg/kg/m i n IV fo r 30 min then 0.05 µg/kg/m i n

Precautions a n d contra i nd i cations

• H istory or c l i n ica l suspicion of i ntracra n i a l bleed i ng, tumor, a rteriovenous ma lforma­tio n , or a n e u rysm

• Peri ca rd itis

• Aortic d i ssection

• Thro m bocytopenia following prior tirofi ban

ad m i n istration

LD, load i ng dose; IV, i ntravenous; CBC, com plete blood count; ACS, ac ute corona ry synd romes; PC I , percutaneous coronary i ntervention; a P PT, activated

partial thromboplastin tim e ; ACT, a ctivated c lotting time; ABW, actua l body weight; CA B G , corona ry a rtery bypass graft; C rC I , creati n i n e clea ra nce

;:l

;:;:

a O"

�

ii" -l

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•t!1:1•::a:I•�• Phosp hod iesterase I nh i b itors

re placement Seconda ry preve ntion i n stroke a nd T I A patients

Dosi ng, t i m i ng, d u ration

100 mg ora l ly twice d a i ly

With concom ita nt wa rfarin thera py:

75-100 mg ora lly fou r times d a i ly

200 mg d i pyridamole, 25 mg aspirin (one capsule) ora l ly twice d a i ly Patients with i nto lera ble headache

200 m g d i pyrida mole, 25 mg aspirin o ra lly d a i ly at bedtime, with 8 1 mg of aspirin i n the morn ing

Retu rn to usual d ose as soon as tolerance to headache develops (usu a l ly with in a wee k)

conges-(Cilostazo l )

CBC, complete blood cou nt; LFT, l iver function tests; TIA, tra nsient ischemic attack; CHF, congestive heart fa i l u re

0 -

(")

• Severe coro n a ry a rtery I

d isease, a bnormal ca rd iac rn

• Coagulation abnormal ities 0

• Hemostatic d isord ers or

-active pathologic b leed i n g (") c ( b leed ing pe ptic u lcer or intrac ra n ial bleed i ng)

Chapter 90 • Antithrombotic Therapy i n Critica l ly I l l Pati ents I 6 7 1

b Cilostazol produces nonhomogenous vasodilation, with greater dilation in femoral beds than in vertebral, carotid, or superior mes­enteric arteries, but without effect in renal arteries

2 Mechanism of action

a Phosphodiesterase inhibition and suppression of cAMP degradation increase cAMP in platelets and blood vessels This causes reversible inhibition of platelet aggregation induced by various stimuli, includ­ing thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress

I I ANTICOAG U LANTS

A Unfractionated heparin (UFH) (Table 90-5)

1 General principles

a Glycosaminoglycan extracted from porcine intestinal mucosa

b Intravenous (IV) administration results in immediate onset with a t112

of 60 to 90 minutes Liver and renal disease prolonged t112•

c Subcutaneous (SC) administration delays onset of action (20 to

60 minutes)

d Heparin resistance occurs in patients who require unusually high heparin doses (>35,000 units/day), to achieve a therapeutic-activated partial thromboplastin time (aPTT), and is attributable to anti­thrombin deficiency, increased heparin clearance, excess heparin­binding proteins, factor VIII, and fibrinogen (Table 90-6)

e Heparin dosing protocols are more effective in achieving goal antico­agulation than an ad hoc approach

a Produced from UFH, with more predictable dose response

b SC administration results in onset of action of20 to 60 minutes with

a t112 of 3 to 6 hours

c Eliminated via the kidneys

d Dosing for obese patients 1s based upon adjusted body weight (AjBW)

•t!1:11•::a:I•&- U nfractionated Heparin

Unfractionated VT E treatment

heparin

ACS treatment

Bridge thera py for atrial

fi bri l l atio n , card ioversion

Pro p hylaxis of VT E in the

m ed ical ly ill or s u rgical

po p u l ation Prophylaxis of VTE in

pregna ncy (with prior VTE)

Dos ing, t i m i ng, duration LD: 80 u n its/kg bolus

1 8 u n its/kg/h infusion adj u sted per local hepa rin n omogra m LD: 6 0 u n its/kg (max 4,000 u n its)

12 u n its/kg/h (max i n itia l dosing 1 , 000 u n its/h) +!- fi bri n s pec ific adj u sted to m a i nta i n

a PTT 1.5 to 2 times control or per local hepa rin n omogra m

I V infusi o n : 60-80 u n its/kg bolus Target a PTT, 60s (ra nge 50-70 s) 5,000 u n its SC q8 h

at least o nce d a i ly

• Anti-Xa level s (a lte r­

native if ava i la ble,

co nsider i n patients with h e pa ri n res ist­

ance or a nti phos­

phol i p i d antibody syn d romes)

• H IT a nti body testing ( not wa rra nted in the a bsence of throm bocytope-

nia, throm bosis, heparin-ind uced skin lesions, or other signs pointi ng to a potentia I d iagnosis

of i m m u n e­

med iated H I T

Precautions and contra indications

Precautions

• Congen ita l or acqu i red b leed i n g d i so rd e rs

• Indwe l l i ng epid u ral cathete r

• G I u l ceration and ongoing tu be d ra i nage of the s m a l l i n testine or stomach

• H e patic d isease with i m pa i red h emostasis

• Hered ita ry a ntith ro m bi n I l l d efic iency a n d concu rrent u s e o f a ntith rom b i n

• Neonates a nd i nfa nts weigh i ng < 1 0 kg

• P rematu re infa nts weig h i n g < l kg

• R i s k of delayed o nset of H IT a nd H ITT Contraindications

d ue to d isseminated intravascular coagu lation

can not be performed at n ecessa ry interva ls

• Patients with i n a rem ote h istory of H I T (> 100 days) cou l d be co nsidered for

a rech a l le nge with heparin provided a negative a nti body test

VTE, venous throm boe m bolism; LD, loa d i n g dose; C BC, co m plete blood cou nt; a PPT, activated partial throm bo plasti n ti m e; ACS, acute coronary synd romes; HIT, hepa rin-ind uced thrombocytopen ia; HITT, h e pari n-ind uced th rom bocyto penia with throm bosis

Chapter 90 • Antith rombotic Therapy i n Critica l ly I l l Patients I 6 7 3

liJ:ii#J.ij Heparin Dose Adj ustment Nomogram

80 u n its/kg bol us, then 18 u n its/kg/h

80 u n its/kg bol us, then i ncrease 4 u n its/kg/h

40 u n its/kg bolus, then i ncrease 2 u n its/kg/h

No cha nge Decrease i nfusion rate by 2 u n its/kg/h Hold i nfusion 1 h , then decrease i nfusion rate by 3 u n its/kg/h

a PTT, activated pa rtial throm boplasti n time

Ada pted from Rasch ke R , Gol l i h a re B , Peirce J The effectiveness of i m plementing the weight-based heparin nomogra m as a practice guideline Arch Intern Med 1996; 1 56 :

1 645-1649

2 Mechanism of action

a Inhibits both factor Xa (predominately) and factor Ha activity

C Factor Xa inhibitors (Table 90-8)

a Well absorbed from the GI tract and 99% bound to plasma albumin

b Hepatically metabolized by cytochrome P450 (CYP) enzymes (mostly 2C9)

c Average half-life is approximately 40 hours but is extremely variable (range: 20 to 60 hours)

d Wide range of dosing required to maintain a therapeutic interna­tional normalized ratio (INR)

e CYP2C9 and VKORC l genetic variation influences patient response

to initial and maintenance therapy and impacts bleeding risk

f Lower doses required for elderly and patients with comorbidities

g Both dietary and drug interactions can influence dosing; frequent monitoring of INR may be required

•t!1:1•::a:I•�• Low M olec u lar We ight Hepa ri ns

SC d a i l y 83-98 kg: 18,000 i nternational u n its

SC d a i l y

>99 k g : 18,000 i nternational u n its

SC d a i l y

120 i nternational u n its/kg SC q l 2 h ( M ax 10,000 internationa l u n its/

dose) 5,000 i nternational u n its SC q 24 h

ing or a bnorma l coagu lation param-eters, pregna nt patients, obese or low-weight patients, and children

bocytope-d iagnosis of H IT)

, -

• H i story of recent major -j

bleed (G I , intracra n ia l , etc ) r

• Congen ita l or acq u i red 0

bleed ing disorders -(")

• Bacteria l e ndoca rd itis "D

• Conco m ita nt use of -j

a ntithrom botic d rugs I

• Dia betic reti nopathy

-• U n control led hyperte nsion (")

c

Low M olec u lar We ight Hepa ri ns (continued)

contra i n d i cations

CrCI < 30 m Um i n : 1 mg/kg SC q 24 h enoxapa ri n , d a lte pa r i n ,

1 mg/kg SC q l 2 h + fi bri nolytic pork p rod ucts, su lfites

CrCI < 30m Um i n : not reco m m ended exci pients

ca rd ioversion CrCI < 30 m Um i n : 1 mg/kg SC q 24 h history of H I T (>100 d )

s u rgica l po pu lation CrCI < 30 m Um i n : 30 mg SC q 24 h provided a negative

anti body test

Prophylaxis of VT E in 30 mg SC q l 2 h

tra u ma patie nts O R

40 m g S C q24 h Renal i m pa i rment:

CrCI < 30 m Um i n : 30 mg SC q 24 h

Ti nza pari n Treatment of DVT 1 7 5 i nternational u n its a nti-Xa/kg

VTE, venous throm boe m bolism; S C , subcuta neous; ACS, acute coronary syn d romes; CBC, complete blood count; CrCI, creati n i n e c lea ra nce; H I T,

hepa rin-ind uced thro m bocytopenia; U F H , unfracti oned hepa rin; STEM I , ST-segment myocard i a l i nfa rction; NST E M I , non ST-segment myoca rd ia l i nfa rction;

UA, u n sta ble a ngina; DVT, deep vein throm bosis

l ::r (1)

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en U1

•t�1:1•::a=1111:• Factor Xa I n h i bitors "'

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Drug I nd ications Dos i ng, t i m i ng, d u ration Mon itoring Precautions and contraind ications

( E l iq u is) patients u ndergoing I n itial d ose 1 2-24 h after su rgery bleed ing • I n dwe l l i ng epid u ra l cathete r -l

6

P ro phylaxis of stroke 32-38 d ( h ip) c reati n i ne • H i story of recent major b leed I

a nd syste m ic e m bo- 5 mg ora l ly twice d a i ly • Anti-Xa levels • Conge n ita l o r acq u i red bleed ing rn

;;::

atrial fibril lation Any two of the fol lowing with sign ifica nt • Hepatic dysfu nction (a pixa ban and -l

0

seru m creati n i ne > 1 5 mg/dU : i m pa i rment, • Conco m ita nt use with strong Gl

2.5 mg orally twice daily those CYP3A4 a n d P-glyco protei n -(") Renal i m pa i rment: experiencing i n h i bitors and i n d u cers (apixa ban "D

CrCI 1 5-29 m Um i n 2 5 mg bleed ing or a n d riva roxa ba n ) ;u

CrCI < 1 5 m Um i n or u n d ergoing coagu lation • Severe active bleed i ng rn

• Bacterial endoca rd itis (/J

Fo nda pa ri nux Treatment of VTE <50 kg: 5.0 mg SC d a i ly pregnant • Body weight <50 kg for prophylactic (A rixtra) 50 to 1 00 kg: 7 5 mg SC d a i ly patients, obese thera py of h i p fracture, h i p replace- z

> 1 00 kg: 1 0 m g SC d a i ly or low-weight ment or knee replacement su rgery, -l Renal i m pa i rment: co nsider patients, or a bdom i n a l su rgery; increased rn

e m p i ric dosage red uction and children risk for major bleed i ng episodes

-(") CrCI 50-80 m Um i n : 25% (agent-specific • Fonda pa r i n ux-re lated c red uction i n tota l clea ra nce assay cali bra- thro m bocyto pen ia

CrCI 30-50 m Um i n : 40 % tion req u i red) • Hypersensitivity to agent or red uction i n tota l clea ra nce form u lation excipients CrCI < 30 mUmin: contraindicated