Labs

Let’s begin with the patient’s complete blood counts (CBCs) over time, beginning with the day of surgery (day 1) and ending on the day you see him (day 12):

DayWBCHbMCVPLTCommentDay
Day 1212.29.19271You are asked to see the patient
Day 11149.49186The first significant drop in platelet count
Day 618.711.988183CTA chest shows large pulmonary embolus, heparin started
Day 114.111.890161Day of surgery

What’s what: WBC, white blood cell count; Hb, hemoglobin; MCV, mean cell volume; MCHC, mean cellular hemoglobin concentration; RDW-SD, red cell distribution width-standard deviation; platelets, PLT; Normal values: WBC 5-10 x 109/L, RBC 4-6 x 1012/L, Hb 12-16 g/dL, Hct 35-47%, MCV 80-100 fL, MCHC 32-36 g/dL, RDW-SD < 45%, platelets (PLT) 150-450 x 109/L. CTA, computed tomography angiography.

Ignoring the details of this case for a moment, and putting aside surgery as a cause of transient postoperative thrombocytopenia, what are the two most common causes of new onset thrombocytopenia in hospitalized patients?

a
Gestational thrombocytopenia
No, this presents in pregnant women in the outpatient setting.
b
Immune thrombocytopenia (ITP)
ITP does not typically present de novo in the inpatient setting.
c
Infection
Correct. Thrombocytopenia may occur with infection in the absence or presence of disseminated intravascular coagulation (DIC).
d
Drugs
Yes. The culprit may include heparin or non-heparin medications.

In the following schematic, thrombocytopenia is classified according to the clinical context:

APS, antiphospholipid syndrome; ITP, immune thrombocytopenia; ICU, intensive care unit; BM, bone marrow; L&D, labor and delivery; TMA, thrombotic microangiopathy.

Here, the likely causes of thrombocytopenia are narrowed down to those associated with inpatient – non-ICU (blue boxes):

APS, antiphospholipid syndrome; ITP, immune thrombocytopenia; ICU, intensive care unit; BM, bone marrow; L&D, labor and delivery; TMA, thrombotic microangiopathy.

We mentioned that infection and drugs are common causes of thrombocytopenia in the hospitalized non-ICU patient. Another cause, which is included in the previous schematic, is postoperative thrombocytopenia resulting from hemodilution and accelerated platelet consumption related to surgical hemostasis. This occurs within 4 days of surgery, well before our patient presented with thrombocytopenia.

For more information on postoperative thrombocytopenia, click here.

Our patient has no evidence of infection. He is afebrile, his other vitals are stable, his chest X-ray does not demonstrate any infiltrates, and his urine is bland. There is no evidence of a surgical wound infection. What then, is the most likely diagnosis?

a
Heparin-induced thrombocytopenia (HIT)
HIT is at the top of the list, as our prediction score will attest to. It is important to rule out the use of other drugs (especially those that have been started in the last several days) that can cause thrombocytopenia, such as vancomycin.
b
Disseminated intravascular coagulation (DIC)
DIC cannot be ruled out. While there is no evidence of an underlying illness associated with DIC (for example, infection or cancer), a small subset of patients with HIT (about 15%) have concomitant DIC.
c
HELLP syndrome
HEELP occurs in women in the perinatal period.
d
Valve hemolysis
This would lead to microangiopathic hemolytic anemia, not thrombocytopenia. Moreover, the patient did not have a history of valve stenosis, repair or replacement.

You carefully examine the medical record and note that the patient has not been started on any new medications since admission with the exception of stool softeners, Tylenol and heparin.

What would you expect the prothrombin time (PT) and activated partial thromboplastin time (aPTT) results to be?

a
PT normal, aPTT elevated
b
PT elevated, aPTT normal
c
PT and aPTT elevated
d
Normal PT and aPTT
Assuming the heparin has been stopped, the majority of patients with heparin-induced thrombocytopenia have normal coagulation assays. That being said, about 15% of patients with HIT have disseminate intravascular coagulation and therefore may have elevated PT +/- aPTT.

The patient’s prothrombin time (PT) is normal, but his activated partial thromboplastin time (aPTT) is elevated. Why?

a
He is still on heparin
Yes… and this should be cause for concern! As we will see, when there is a high suspicion for heparin-induced thrombocytopenia, all heparin products must be stopped immediately.
b
He has disseminated intravascular coagulation (DIC)
The PT is more commonly increased than the aPTT. But DIC cannot be ruled out.
c
The patient has a lupus anticoagulant
A lupus anticoagulant might explain a predisposition to pulmonary embolism in the postoperative period, as well as the elevated aPTT, but common things being common, the ongoing administration of heparin is a much more likely explanation.

You are concerned about a diagnosis of heparin-induced thrombocytopenia. What scoring system would you use to determine the pretest probability of this disorder?

a
PLASMIC score
Used to determine pretest probability of thrombotic thrombocytopenia purpura (TTP).
b
HScore
Used for the diagnosis of hemophagocytic lymphohistiocytosis (HLH).
c
4T score

What clinical parameters are included in the 4T score?

a
Timing of platelet count drop
b
Tissue hypoperfusion
Not included in the 4T score
c
Thrombocytopenia
d
Thrombosis
e
Other causes of thrombocytopenia

What are the T’s in the 4T score?

Let’s take a closer look at the 4T score:

Parameter2 points1 point0 pointsComments
Thrombo-
cytopenia
Platelet count fall > 50% AND platelet nadir ≥ 20 × 109 L−1Platelet count fall 30%–50% OR platelet nadir 10–19 × 109 L−1Platelet count fall < 30% OR platelet nadir < 10 × 109 L−1Fall from highest platelet count that immediately precedes the putative HIT-related platelet count fall. 95% of cases of HIT are reported to develop in temporal association with heparin therapy; typically > 50% platelet count fall, but not to levels < 20 × 10 9 /L; only a few patients show 30%-50% platelet count fall; typical nadir is 40-80 × 109/L, with median of 55 × 109/L.
Timing of platelet count fall

Clear onset between days 5 and 10 OR platelet fall ≤ 1 day (in the case of prior heparin exposure within 30 days)Consistent with days 5–10 fall, but not clear (e.g. missing platelet counts) OR onset after day 10 OR fall ≤ 1 day (prior heparin exposure 30–100 days ago)Platelet count fall < 4 days without recent heparin exposureDay 5 to 10 for initial platelet count fall with day 0 representing first heparin exposure; earlier fall if patient exposed to heparin with previous 30 days. Days are rounded off. For example, day 4.3 would count as day 4.
Thrombosis or other sequelae

New thrombosis (confirmed) OR skin necrosis at heparin injection sites OR acute systemic reaction after intravenous heparin bolusProgressive or recurrent thrombosis or non-necrotizing (erythematous) skin lesions or suspected thrombosis (not provenNone
Other causes for thrombocytopeniaNone apparentPossibleDefinite

Scoring 0, 1, or 2 points for each of 4 categories, maximum possible score = 8:

  • Low score 0-3 points
  • Intermediate score 4-5 points
  • High score 6-8 points

Low 4Ts score may rule out HIT but high 4Ts score may not be sufficient to diagnose HIT.

The 4T score is used to estimate the pretest probability of having heparin-induced thrombocytopenia (HIT). The following table shows the negative and positive predictive values of the 4T score for diagnosis of HIT:

NPV, negative predictive value; PPV, positive predictive value

The next step in the work up of this patient is to determine his 4T score (next slide).

Parameter2 points1 point0 pointsOur patient
ThrombocytopeniaPlatelet count fall > 50% AND platelet nadir ≥ 20 × 109 L−1Platelet count fall 30%–50% OR platelet nadir 10–19 × 109 L−1Platelet count fall < 30% OR platelet nadir < 10 × 109 L−1This patient’s platelet count fell from 183 x 109/L to 71 x 10 9 /L; that amounts to a 60% drop. The nadir was > 20 x 109/L. Therefore, he receives 2 points.
Timing of platelet count fall

Clear onset between days 5 and 10 OR platelet fall ≤ 1 day (in case of prior heparin exposure within 30 days)Consistent with days 5–10 fall, but not clear (e.g. missing platelet counts) OR onset after day 10 OR fall ≤ 1 day (prior heparin exposure 30–100 days ago)Platelet count fall < 4 days without recent heparin exposurePlatelets in this case fell 5 days following initiation of heparin. Therefore, he receives 2 points.
Thrombosis or other sequelae

New thrombosis (confirmed) OR skin necrosis at heparin injection sites OR acute systemic reaction after intravenous heparin bolusProgressive or recurrent thrombosis or non-necrotizing (erythematous) skin lesions or suspected thrombosis (not provenNoneThe patient was diagnosed with pulmonary embolus, but this preceded initiation of heparin and does not count in the 4T score. Therefore, he receives no points.
Other causes for thrombocytopeniaNone apparentPossibleDefiniteOur patient did not have any apparent other cause for thrombocytopenia. Therefore, he receives 2 points.
Total score6 – high probability score

This patient’s score of 6 qualifies as a high score.

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Before moving on, let’s test you recall with a sorting exercise. Drag and drop the parameters on top to the proper buckets on the bottom:

Timing
Thrombotic microangiopathy (TMA)
HIT antibody result
Serotonin release assay
TTP
Thrombocytopenia
Thrombosis
Other causes of thrombocytopenia
Part of the 4T score
Not part of the 4T score

The patient’s 4T score of 6 amounts to a high risk score with a positive predictive value of 64%. What other lab tests would you recommend?

a
HIT antibodies
Correct. A high 4T score calls for testing for HIT antibodies.
b
Serotonin release assay
Not yet! More on the serotonin assay shortly.
c
Doppler of legs
2018 ASH clinical practice guideline: “In patients with acute isolated HIT, the ASH guideline panel suggests bilateral lower-extremity compression ultrasonography to screen for asymptomatic proximal deep vein thrombosis (DVT)… dopplers of upper extremity if upper-extremity central venous catheter (CVC) to screen for asymptomatic DVT.” That being said, the patient has already been diagnosed with a pulmonary embolus, and so further screening (which is done to determine length of anticoagulation) is not necessary.1
d
Platelet electron microscopy
This assay is typically reserved for investigation of congenital thrombocytopenia.

As shown in the schematic below, an intermediate/high 4T score should prompt an immunoassay. An intermediate/high 4T score also influences treatment decisions (discussed in the next section).