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Case 3. Warfarin Monitoring in Special Circumstances

Case 3. Warfarin Monitoring in Special Circumstances

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513



Anticoagulation Drugs: Indications, Therapeutic Monitoring, and Antidotes

Table 10 Phase III clinical trials of DOACs for prevention of VTE in joint replacement



Trial

ADVANCE-1

(TKA)

(Lassen et al. 2009)



Study arms

Apixaban 2.5 mg BID

vs. enoxaparin 30 mg sc

QD (3195)



Duration (days)

10–14



ADVANCE-3

(THA)

(Lassen et al. 2010)

RECORD2

(THA)

(Kakkar et al. 2008)

RECORD3

(TKA)

(Lassen et al. 2008)

RE-NOVATE

(THA)



Apixaban 2.5 mg BID

vs. enoxaparin 40 mg sc

QD (5407)



32–38



Rivaroxaban 10 mg QD

vs. enoxaparin 40 mg sc

QD



(Eriksson et al.

2007a, b)



RE-MODEL

(TKA)



VTE risk

9 % vs. 8.8 %



Major and

clinically relevant

nonmajor

bleeding

2.9 % vs. 4.3 %



(p = 0.06 for

noninferiority)

1.4 % vs. 3.9 %

(p < 0.001)



3.5%vs. 4.8 %

(p = 0.72)



31–39

(rivaroxaban) vs.

10–14



2.0 % vs. 9.3 %

(p < 0.0001)



6.6 % vs. 5.5 %

(p = 0.25)



Rivaroxaban 10 mg OD

vs. enoxaparin 40 mg sc

QD (2531)



10–14



9.6 % vs. 18.9 %

(p < 0.001)



4.9 % vs. 4.8 %

(p = 0.93)



Dabigatran 150 mg or

220 mg QD (halfquantity first dose) or

enoxaparin 40 mg sc QD



28–35



8.6 % and 6.0 % vs.

6.7 %

(p < 0.001 for

noninferiority)



Dabigatran 150 mg or

220 mg QD (halfquantity first dose) or

enoxaparin 40 mg sc QD



6–10



40.5 % and 36.5 % vs.

37.7 %

(p = 0.017 and

p = 0.0003)



1.3 % and 2 %

vs. 1.6 %

(Major

bleeding)

(p = 0.6 and

0.44)

1.3 % and 1.5 %

vs. 1.3 %

(major

bleeding)

(p = 1.0 and

0.82)



(Eriksson et al.

2007a, b)



6–12 h, or even preoperatively as in the case of

LMWH. Table 10 summarizes some major trials

in this field. As for other indications, patient

comorbidities, particularly renal dysfunction,

drug interactions, and concomitant use of antiplatelet agents, are all important factors to consider prior to selecting an agent. This patient was

treated with 40 mg enoxaparin subcutaneous

daily for 2 weeks.

Question 9. A month after her surgery, the

patient suffers a prosthetic joint infection. She

requires a joint explant and is now in a nursing

home. She receives thromboprophylaxis with

UFH 5000 units subcutaneously every 8 h. She is

considerably deconditioned and now weighs

48 kg. One morning she is found on the floor and

rushed to the hospital. Head imaging reveals a

right parietal intraparenchymal bleed. Her coagu-



(p = 0.03)



lation tests are notable for an aPTT 140 s, PT

15 s, TT 100 s, and fibrinogen 280 mg/ml.

How should her coagulopathy be best

managed?

A. Plasma

B. PCC

C. rFVIIa

D. Protamine

Expert

Perspective Prophylactic

heparin

administration has been shown to prevent thrombosis in hospitalized medically ill patients.

Although the recommended doses of UFH, 5000

units every 8–12 h, are considered safe and effective and do not typically require monitoring, an

occasional patient may benefit from laboratory

monitoring to prevent overdose. Table 11



A.V. Sharda and J.I. Zwicker



514

Table 11 Clinical pharmacology of unfractionated

heparin

Pharmacokinetics

Onset of action

Half-life



Metabolism/elimination

Excretion

Pharmacodynamics

Mechanism of action

Therapeutic goal



iv: immediate; sc:

20–30 min

Dose dependent; mean

1.5 h; affected by renal

function, total protein,

infection,

inflammation,

malignancy, obesity

Hepatic and RES

Small amount in urine

Indirect thrombin

inhibitor

1.5–2.5 times the upper

range of normal aPTT

or anti-factor Xa level

of 0.3–0.7 U/ml



RES reticuloendothelial system



summarizes pharmacokinetics and pharmacodynamics of UFH. The pharmacology of LMWH is

being discussed elsewhere in “Anticoagulation

Issues in Oncology.”

This clinical picture is highly suspicious for

heparin overdose. The patient received 50 mg of

protamine sulfate and her aPTT and TT normalized

rapidly. Other coagulation parameters drawn prior

to administration of protamine returned with reptilase time 17 s (normal <20) and chromogenic antifactor Xa (or UFH assay) of 2.5 U/ml. At 12 h these

levels were 0.2 U/ml and rapidly disappeared. One

milligram of protamine neutralizes about 100 units

of UFH. Generally, the dose is estimated for UFH

administered within the previous 2 h. Protamine

overdose can result in coagulopathy, as studied in

cardiac surgery, and requires careful titration.

Protamine does not have any effect on plasma antiXa levels and, at best, may reverse LMWH coagulopathy partially (Garcia et al. 2012).

Question 10. Despite being eligible for all, the

patient chose warfarin. Three months into

therapy, his therapeutic control remains

labile, now made worse by amiodarone initiated for symptomatic persistent atrial fibrillation. He needs PT/INR tested twice weekly.

How should this case be managed?



Expert Perspective The need for repeated lab

monitoring remains one of the more common

reasons for patient disapproval of warfarin. In

addition to sub- and supra-therapeutic INR levels, variability of INR over time independently

predisposes one to risks of thromboembolic and

bleeding events. Dietary factors, alcohol intake,

drug interactions (CYP2C9 interactions), and

intercurrent illnesses all influence warfarin pharmacokinetics and INR levels. Knowledge of

these factors help in managing warfarin better.

Needless to say, an experienced warfarin clinic is

invaluable in managing such cases.

With the approval of DOACs, management of

these cases has become easier.

Answer

Question 3. E

Question 6. D

Question 7. C

Question 8. B

Question 9. D



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Heparin-Induced

Thrombocytopenia: Diagnosis

and Management

Lova Sun and Adam Cuker



Introduction

Heparin-induced thrombocytopenia (HIT) is a

prothrombotic adverse reaction to heparin mediated by platelet-activating antibodies that target

multimolecular complexes of platelet factor 4

(PF4) and heparin.

Diagnosis is based on both clinical and laboratory criteria. The pretest probability of HIT may

be estimated using the 4T score, a validated clinical scoring system for HIT. Laboratory tests for

HIT fall into two categories: immunoassays and

functional assays. Immunoassays such as the HIT

enzyme-linked immunosorbent assay (ELISA)

are widely used in clinical practice and have high

sensitivity but are unable to distinguish platelet-



L. Sun

Department of Medicine, Perelman School of

Medicine, University of Pennsylvania,

Philadelphia, PA, USA

e-mail: lovasun@gmail.com

A. Cuker (*)

Department of Medicine, Perelman School of

Medicine, University of Pennsylvania,

Philadelphia, PA, USA

Department of Pathology & Laboratory Medicine,

Perelman School of Medicine, University of

Pennsylvania, Philadelphia, PA, USA

Department of Medicine and Department

of Pathology & Laboratory Medicine,

Hospital of the University of Pennsylvania,

3400 Spruce Street, Philadelphia, PA 19104, USA

e-mail: adam.cuker@uphs.upenn.edu



activating antibodies from their more common

nonpathogenic counterparts. Functional assays

such as the 14C-serotonin release assay (SRA) are

more specific and may be used to confirm the

diagnosis but are not widely available.

Treatment of HIT involves discontinuation of

heparin and initiation of a parenteral non-heparin

anticoagulant. The direct thrombin inhibitor argatroban is the only FDA-approved agent for the

treatment of HIT available in the USA. There is

growing off-label use of fondaparinux and

bivalirudin.

In this chapter, we discuss our approach to

commonly encountered clinical dilemmas in the

diagnosis and management of HIT and HITassociated thrombosis. We address diagnosis and

initial management, including options for parenteral anticoagulation. We also focus on transition

to oral anticoagulants, duration of anticoagulation, platelet transfusion, and re-exposure to heparin in patients with a history of HIT.



Case

You are consulted for new thrombocytopenia in a

70-year-old man who underwent total hip

replacement 8 days ago. The patient has been

receiving prophylactic enoxaparin at a dosage of

40 mg SC every 24 h since the day before surgery.

There is no history of recent heparin exposure

prior to surgery. His platelet count, which was

185 × 109/L on the day of the operation and



© Springer International Publishing Switzerland 2016

S.A. Abutalib et al. (eds.), Nonmalignant Hematology, DOI 10.1007/978-3-319-30352-9_45



519



L. Sun and A. Cuker



520



170 × 109/L on the seventh postoperative day, is

55 × 109/L this morning. He is on hydrochlorothiazide for hypertension and acetaminophen/

oxycodone for postoperative pain management.

He was started on trimethoprim/sulfamethoxazole for a postoperative wound infection 5 days

ago. On exam, he appears well. There are no skin

changes or stigmata of bleeding or thrombosis.

The surgical site is clean and dry with minimal

erythema.

Question 1. Which of the following is a characteristic clinical feature of HIT?

A. Petechiae and mucocutaneous bleeding

B. Severe thrombocytopenia (platelet count

<20 × 109/L)

C. Erythematous lesions at subcutaneous heparin injection sites

D. A fall in platelet count of 30 % or less

E. A fall in platelet count beginning 5–10 days

after heparin exposure

Expert Opinion Key clinical features suggestive

of HIT are shown in Table 1. A ≥50 % fall in the



platelet count, measured from the peak platelet

count after initiation of heparin to the nadir platelet count, is a characteristic of HIT. The thrombocytopenia associated with HIT is characteristically

mild to moderate; the median nadir platelet count

is ~60 × 109/L, and the platelet count need not fall

below the traditional threshold for thrombocytopenia (i.e., 150 × 109/L). In heparin-nạve patients,

the platelet count fall typically begins 5–10 days

after initiation of heparin. Patients with previous

recent heparin exposure (usually within the last

30 days) who have preexisting circulating HIT

antibodies are at risk for rapid onset HIT, in which

the platelet count falls immediately upon re-exposure to heparin. Rarely, the platelet count may fall

several days to weeks after heparin has been discontinued

(delayed-onset

HIT).

Thromboembolism is clinically apparent in

20–50 % of patients at diagnosis and may precede

the onset of thrombocytopenia (Greinacher et al.

2005). Even after heparin is discontinued, the risk

of thrombosis persists at least until platelet count

recovery and for up to 30 days (Warkentin and

Kelton 1996). Venous thromboembolism is

more common than arterial thrombosis



Table 1 Clinical features suggestive of HIT

Manifestation

≥50 % fall in platelet count

Platelet count nadir ≥20 × 109/L



Fall in platelet count begins 5–10 days

after heparin exposure

Venous or arterial thrombosis

Skin necrosis

Anaphylactoid reaction

Absence of alternative causes of

thrombocytopenia

Absence of petechiae and other

mucocutaneous bleeding



Notes

Measured from highest platelet count after heparin exposure

In ~10 % of cases, platelet count falls only 30–50 %

Median nadir platelet count is ~60 × 109/L

Nadir need not meet the traditional definition of thrombocytopenia (i.e.,

<150 × 109/L) in patients with high baseline platelet counts

In cases associated with DIC, platelet count may be <20 × 109/L

Platelet fall may occur within 24 h (“rapid-onset” HIT) in patients with

previous heparin exposure in last 100 days

Occurring ≥5 days after heparin administration and up to 30 days after

heparin cessation

At subcutaneous heparin injection sites. Non-necrotizing erythematous

skin lesions are due to type IV hypersensitivity reactions and not to HIT

Within 30 min after intravenous heparin bolus or subcutaneous injection

Common alternative causes include other medications that cause

thrombocytopenia, infection, recent cardiopulmonary bypass, intraaortic balloon pump, extracorporeal membrane oxygenation

Adrenal hemorrhage secondary to adrenal vein thrombosis may occur in

association with HIT



DIC disseminated intravascular coagulation, HIT heparin-induced thrombocytopenia



Heparin-Induced Thrombocytopenia: Diagnosis and Management



(Greinacher et al. 2005). Less common clinical

manifestations include skin necrosis at subcutaneous heparin injection sites, anaphylactoid reactions, adrenal hemorrhage secondary to adrenal

vein thrombosis, and transient global amnesia

(Warkentin et al. 2005). HIT is rarely associated

with serious spontaneous bleeding. The presence

of petechiae and mucocutaneous bleeding should

be regarded as evidence against HIT and prompt

consideration of alternative causes of thrombocytopenia (Cuker and Cines 2012).

Question 2. According to the 4T scoring system, what is the patient’s pretest probability

of HIT?

A.

B.

C.

D.



Low

Intermediate

High

Cannot be determined



Expert Opinion It is difficult to incorporate the

clinical manifestations listed in Table 1 into an

estimate of the clinical likelihood of HIT. Several

scoring systems have been developed to facilitate

this process (Lo et al. 2006; Cuker et al. 2010).

The most extensively studied of these is the 4T

score. Patients are assigned a score of 0, 1, or 2

across four categories: thrombocytopenia, timing, thrombosis of other sequelae, and other

causes of thrombocytopenia. The summative

scores of 0–3, 4–5, and 6–8 correspond to a low,

intermediate, and high pretest probability of HIT,

respectively (Table 2). In a meta-analysis of 13

studies involving 3068 patients, the negative predictive value of a low probability 4T score was

99.8 % (95 % CI 97.0–100), whereas the positive

predictive value of an intermediate and high

probability 4T score was 14 % and 64 %, respectively (Cuker et al. 2012).

We would assign the patient in the Case 2

points for thrombocytopenia (platelet fall

≥50 % and nadir ≥20 × 109/L), 2 points for timing (platelet fall onset 5–10 days after initiation of heparin), 0 points for thrombosis or

other sequelae, and 1 point for other causes of



521



thrombocytopenia (drugs, especially trimethoprim/sulfamethoxazole), yielding a score of

5, which places him in the intermediate probability category.



Question 3. The patient is determined to have

an intermediate probability of HIT. What are

the next appropriate steps in his evaluation

and management?

A. Continue enoxaparin, order HIT laboratory

testing

B. Stop enoxaparin, order HIT laboratory

testing

C. Stop enoxaparin, start an alternative

anticoagulant

D. Stop enoxaparin, start an alternative anticoagulant, order HIT laboratory testing



Expert Opinion Our approach to the initial

evaluation and management of patients with suspected HIT is shown in Fig. 1 (Cuker and Cines

2012). Because of its high negative predictive

value (Cuker et al. 2012), a low probability 4T

score essentially excludes HIT. Patients may

remain on heparin and alternative etiologies of

thrombocytopenia should be sought. In patients

with an intermediate or high probability 4T score,

all heparin products (including low-molecularweight heparin, heparin flushes, and heparinbonded catheters) should be discontinued, HIT

laboratory testing should be ordered, and, barring

a contraindication, an alternative anticoagulant

should be initiated while awaiting laboratory test

results.

Question 4. Which of the following anticoagulants is not an appropriate option for the

patient at this time?

A.

B.

C.

D.

E.



Warfarin

Argatroban

Bivalirudin

Fondaparinux

Danaparoid



L. Sun and A. Cuker



522

Table 2 4T scoring system for HIT

Category

Thrombocytopenia



2 points

>50 % fall in platelets and

nadir ≥20 × 109/L



Timing of platelet fall



Clear onset of fall

between days 5 and 10

after heparin exposure or

within 1 day (if prior

exposure within 30 days)

New confirmed

thrombosis or skin

necrosis or acute

anaphylactoid reaction

after IV heparin bolus

None apparent



Thrombosis or other sequelae



Other causes of

thrombocytopenia



1 point

30–50 % fall in platelets

or platelet nadir

10–19 × 109/L

Timing consistent with

day 5–10 but unclear or

onset after day 10 or

within 1 day (if prior

exposure 30–100 days)

Progressive, recurrent, or

silent thrombosis;

erythematous skin

lesions; suspected

thrombosis

Possible



0 points

<30 % fall in

platelets or nadir

<10 × 109/L

Platelet count fall

≤4 days after

heparin exposure

(with no other recent

heparin exposure)

None



Definite



6–8 points = high probability;|4–5 points = intermediate probability;|≤3 points = low probability



HIT Suspected



4T score ≥4 (Intermediate/high clinical probability)

→ Stop heparin; start alternative anticoagulant

→ Obtain HIT ELISA



Strongly positive (OD ≥ 1) or

weakly positive (OD 0.4-0.99)

with 4T score ≥6

→ Obtain functional assay



Weakly positive

(OD 0.4-0.99)

with 4T score 4-5



4T score ≤ 3

(Low clinical

probability)



Negative



HIT unlikely

Functional assay

positive



Functional assay

negative



HIT likely



HIT indeterminate



→ Consider

alternative

diagnoses

→ Continue

heparin



Fig. 1 Diagnostic and initial treatment algorithm for suspected HIT. ELISA enzyme-linked immunosorbent assay, OD

optical density



Expert Opinion Anticoagulant options for

patients with acute HIT and dosing and monitoring recommendations are shown in Table 3.



Argatroban is the only FDA-approved treatment

for HIT (Lewis et al. 2006). Danaparoid is

approved in Canada, Europe, and Australia but is



523



Heparin-Induced Thrombocytopenia: Diagnosis and Management

Table 3 Alternative anticoagulants for the treatment of HIT

Agent

Argatroban



Danaparoid



Class

Direct

thrombin

inhibitor



Indirect Xa

inhibitor



Initial dosing

Bolus: none



Monitoring

Adjust dose to APTT

of 1.5–3.0 times

patient baseline



Continuous infusion

Normal organ function

→2 mcg/kg/min

Hepatic dysfunction (total

bilirubin >1.5 mg/dL), heart

failure, post cardiac surgery,

anasarca →0.5–1.2 mcg/kg/

min

Bolus



Check APTT every

4 h during titration



<60 kg →1500 U



Bivalirudin



Direct

thrombin

inhibitor



Fondaparinux



Indirect Xa

inhibitor



60–75 kg →2250 U

75–90 kg →3000 U

>90 kg →3750 U

Accelerated initial infusion

400 U/h × 4 h, then

300 U/h × 4 h

Maintenance infusion

Cr <2.5 mg/dL →200 U/h

Cr ≥2.5 mg/dL →150 U/h

Bolus: none

Continuous infusion

Normal organ function

→0.15 mg/kg/h

Renal/hepatic insufficiency →

dose reduction may be

necessary

<50 kg →5 mg SC daily

50–100 kg: →7.5 mg SC daily

>100 kg →10 mg SC daily

Cr clearance 30–50 ml/min →

use caution

Cr clearance <30 ml/min →

contraindicated



Notes

Preferred in patients

with renal

insufficiency

(hepatically cleared)

Prolongs PT/INR



Adjust dose to

danaparoid-specific

anti-Xa activity of

0.5–0.8 U/ml



Not available in the

USA

Long half-life

(~25 h)

Renally cleared



Adjust dose to APTT

of 1.5–2.5 times

patient baseline



Not approved for

treatment of acute

HIT



We do not monitor

routinely

Some experts

recommend adjusting

dose to a peak

fondaparinux-specific

anti-Xa activity of

1.5 U/mL



Most suitable for

stable patients who

are not at increased

bleeding risk and

are unlikely to

require an emergent

surgical intervention



APTT activated partial thromboplastin time, INR international normalized ratio, PT prothrombin time



not available in the USA (Chong et al. 2001).

Bivalirudin and fondaparinux are not approved

for treatment of acute HIT, but successful offlabel use has been reported (Joseph et al. 2014;

Kang et al. 2015). In acutely ill patients, we prefer argatroban if liver function is intact and bivalirudin if there is hepatic impairment because of

the relatively short half-life of these agents. In



more stable patients who do not have elevated

bleeding risk and who are unlikely to require

emergent surgical intervention, we prefer

fondaparinux because of the convenience of once

daily SC administration. There are several case

reports of fondaparinux causing or exacerbating

HIT, but the totality of evidence suggests this is

very rare.



L. Sun and A. Cuker



524



Warfarin and other VKAs should never be

used in patients with acute HIT because of the

potential for venous limb gangrene (Warkentin

et al. 1997). Direct oral anticoagulants (DOACs)

such as dabigatran, rivaroxaban, apixaban, and

edoxaban are currently under investigation for

the treatment of acute HIT (Linkins et al. 2014).

Until data become available, DOACs should be

avoided in this setting outside of a clinical trial.

Whenever possible, inferior vena cava filters

should also be avoided in patients with acute

HIT because they may promote caval

thrombosis.

It is important to emphasize that patients with

a low probability 4T score as well as those in

whom HIT has been excluded by laboratory testing should receive heparin if parenteral anticoagulation is indicated (Fig. 1). Alternative

anticoagulants should not be used because of disadvantages including increased bleeding risk,

irreversibility, and greater cost.

Question 5. Enoxaparin is stopped and argatroban is initiated. Which diagnostic laboratory test would be most appropriate to send at

this time?

A.

B.

C.

D.



Anti-Xa assay

HIT ELISA

Thrombin time

Thrombin generation assay



Expert Opinion Laboratory tests for HIT fall

into two categories: immunologic assays and

functional assays. Immunologic assays such as

the HIT ELISA detect circulating anti-PF4/heparin antibodies and are highly sensitive but have

limited specificity because they are unable to

discriminate potentially pathogenic plateletactivating antibodies from nonpathogenic antibodies (Amiral et al. 1992; Pouplard et al. 1999).

Functional assays such as the SRA and heparininduced platelet activation assay have greater

specificity but are technically demanding and are

only performed at select reference laboratories,

often with turnaround times of several days.



Because anti-PF4/heparin antibodies of the

IgG class are primarily responsible for HIT

(Greinacher et al. 2007), restriction of antibody

detection to the IgG class has been studied as a

means of improving specificity. Compared with

the polyspecific HIT ELISA which detects antibodies of the IgG, IgA, and IgM classes, the IgGspecific ELISA improves specificity but at the

possible cost of reduced sensitivity (Cuker and

Ortel 2009). Novel rapid immunoassays such as

the particle gel immunoassay offer turnaround

times of less than 30 min and have the potential

to improve the speed of HIT exclusion and curb

overtreatment (Linkins et al. 2012).

We request an immunologic assay such as the

HIT ELISA in all patients with an intermediate or

high probability 4T score (Fig. 1). If the test is

negative, HIT is essentially excluded. If it is positive, we order a functional assay to confirm the

diagnosis.

Question 6. The HIT ELISA result comes

back the next day as “positive” with an optical

density (OD) of 1.60 (normal <0.40). What do

you conclude?

A. The patient has HIT.

B. HIT is ruled out.

C. Still indeterminate.

Expert Opinion As noted above, a positive

ELISA in a patient suspected of HIT is generally

not sufficient for definitive diagnosis and requires

a confirmatory functional assay. Whenever possible, ELISA results should be reported in OD

units (Watson et al. 2012), since OD is directly

correlated with the risk of thrombosis (Zwicker

et al. 2004) and the likelihood of a positive functional assay (Warkentin et al. 2008). In one study,

only 1 of 37 patient samples exhibiting a weakly

positive OD (0.40–0.99) tested positive by SRA

in contrast to 33 of 37 with a strongly positive

ELISA (≥2.00) (Warkentin et al. 2008). We use

the OD value in conjunction with clinical information to guide evaluation and management

(Fig. 1).



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