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Von Willebrand, HIT, DIC and anticoagulant assays

15 min

Skills you'll build4 skills
  • Classify a von Willebrand panel from antigen, activity ratio, and factor VIII
  • Sequence HIT immunoassay and functional testing by pretest probability
  • Recognize the platelet, PT, D-dimer, and fibrinogen changes that suggest DIC
  • Choose the calibrated assay that measures a stated heparin or direct oral anticoagulant

At the bench: Review coagulation results and identify the next laboratory check

Try first

Try first

A von Willebrand factor (VWF) panel shows VWF antigen 55 IU/dL and platelet-dependent VWF activity 30 IU/dL, an activity-to-antigen ratio of 0.55. Factor VIII activity is 48 IU/dL. What does this ratio support?

Keep going to see the reasoning.

Right. Keep going to follow the reasoning.

Keep going to see the reasoning.

Keep going to see the reasoning.

Get the idea

Use the explanation to check your first decision.

Classifying a VWF panel

The initial VWD panel combines VWF antigen, platelet-dependent VWF activity, and factor VIII activity. An activity-to-antigen ratio below 0.7 supports a qualitative type 2 defect. A ratio at or above 0.7, with both values proportionately reduced, fits type 1. Multimer analysis or collagen-binding activity then separates the type 2 subtypes.1

HIT testing and pretest probability

The 4Ts score assesses the degree of thrombocytopenia, timing after heparin exposure, thrombosis, and competing causes. With an intermediate or high score, a PF4-heparin immunoassay screens first. A positive immunoassay shows binding antibody. A functional assay, such as the serotonin-release assay, shows activation at a low heparin concentration that saturating heparin suppresses. This heparin-dependent pattern confirms heparin-induced thrombocytopenia (HIT).2

Recognizing DIC

Disseminated intravascular coagulation (DIC) needs a compatible trigger together with falling platelets, a lengthening prothrombin time (PT), a raised D-dimer, and falling fibrinogen. The 2025 International Society on Thrombosis and Haemostasis (ISTH) score scales each component against the assay's own D-dimer upper limit of normal, and a total of 5 or more is compatible with overt DIC in the right setting.3 A raised D-dimer without the trigger and the other changes does not establish DIC.

Matching the anticoagulant to its assay

Anti-Xa results are quantitative only against the drug's own calibrator. A heparin-calibrated anti-Xa assay falsely raises a result for apixaban or rivaroxaban, and neither the PT nor the APTT can quantify either drug.4 A drug-calibrated anti-Xa assay measures direct factor Xa inhibitors, and a dilute thrombin time or an ecarin-based assay measures dabigatran.

Follow the bench demonstration

Sources for this step
References
  1. James PD, Connell NT, Ameer B, et al. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv. 2021;5(1):280-300. doi:10.1182/bloodadvances.2020003265
  2. Cuker A, Arepally GM, Chong BH, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv. 2018;2(22):3360-3392. doi:10.1182/bloodadvances.2018024489
  3. Iba T, Levy JH, Maier CL, et al. Updated definition and scoring of disseminated intravascular coagulation in 2025: communication from the ISTH SSC Subcommittee on Disseminated Intravascular Coagulation. J Thromb Haemost. 2025;23(7):2356-2362. doi:10.1016/j.jtha.2025.03.038
  4. Douxfils J, Adcock DM, Bates SM, et al. 2021 update of the International Council for Standardization in Haematology recommendations for laboratory measurement of direct oral anticoagulants. Thromb Haemost. 2021;121(8):1008-1020. doi:10.1055/a-1450-8178

Watch one

Read each decision and its explanation.

A patient's platelet count has fallen more than 50% from baseline, with a nadir of 35 × 10³/µL, beginning 7 days after starting unfractionated heparin for a different indication. No other cause of thrombocytopenia is apparent.

  1. Score the 4Ts. A fall greater than 50% with this nadir, this timing, and no competing cause gives an intermediate or high score.

    The 4Ts score assesses these features and sets the pretest probability before testing.

  2. Proceed with testing, since the score is intermediate or high.

    Testing at a low pretest probability risks a false-positive antibody result being treated as HIT, so the score determines whether to test.

  3. Order the PF4-heparin immunoassay first.

    The immunoassay is sensitive and a reasonable first test, but it detects binding antibody that may or may not activate platelets.

  4. If the immunoassay is positive, order a functional assay, such as the serotonin-release assay, before treating the result as confirmed HIT.

    Only a functional assay shows the heparin-dependent activation pattern that distinguishes a platelet-activating antibody from a nonactivating one.

Test in this order: the PF4-heparin immunoassay first, then a functional assay to confirm platelet activation, because the 4Ts score gives a pretest probability that supports testing.

Practice this skill

Your turn

Problem 1 of 3 · Hints available

In a patient with sepsis, platelets are 40 × 10³/µL, D-dimer is 5 times the assay's upper limit of normal (ULN), PT is 4 seconds above control, and fibrinogen is 120 mg/dL. What is the 2025 ISTH disseminated intravascular coagulation (DIC) score, and what does it mean?

Incorrect. A total of 4 comes from scoring the platelet count of 40 × 10³/µL as 1 point. A count below 50 × 10³/µL scores 2.

Correct. Platelets below 50 × 10³/µL score 2, D-dimer above 3 to 7 × ULN scores 2, a PT prolongation of 3 to below 6 seconds scores 1, and fibrinogen of 100 mg/dL or higher scores 0. Sepsis supplies the compatible trigger the score requires.

Incorrect. Fibrinogen scores 1 point only below 100 mg/dL, so 120 mg/dL scores 0.

Hint
  1. Score each component separately against its own thresholds before adding them.
  2. The D-dimer component is scaled against the assay's own upper limit of normal.

Review Disseminated intravascular coagulation

Problem 2 of 3 · Hints available

A PF4-heparin immunoassay is positive on a patient with a low 4Ts score. What does this result mean?

The immunoassay detects binding antibody, and only a functional assay shows platelet activation. At a low pretest probability a positive screen is most often a false positive.

Read a positive PF4-heparin immunoassay as confirmed HIT

A PF4-heparin immunoassay detects binding antibody, including antibody that does not activate platelets. A functional assay such as the serotonin-release assay shows activation at low heparin that saturating heparin suppresses, which identifies a platelet-activating antibody. Testing starts only when the clinical 4Ts score is intermediate or high.

The immunoassay detects binding antibody, and many patients with a low 4Ts score have antibody that does not activate platelets. The positive screen is interpreted with the low pretest probability, and a functional assay confirms HIT if it remains suspected.

The immunoassay shows binding antibody only. Confirmation of HIT comes from a functional assay.

Hint
  1. Consider what the immunoassay detects and how a low pretest probability affects a positive result.
  2. Pretest probability changes what a positive screen means.

Review Thrombophilia and heparin-induced thrombocytopenia

Problem 3 of 3 · On your own

A patient on rivaroxaban has an anti-Xa result reported from a heparin-calibrated assay. The care team wants to use it to judge whether the drug level is therapeutic. What do you tell them?

A heparin-calibrated anti-Xa assay is falsely raised by rivaroxaban and does not give a quantitative rivaroxaban level.

Reported a DOAC level from a heparin-calibrated anti-Xa

Anti-Xa results are quantitative only against the drug's own calibrator. Apixaban or rivaroxaban falsely raises a heparin-calibrated anti-Xa result, and PT or APTT cannot quantify either drug. A drug-calibrated anti-Xa measures direct Xa inhibitors, and a dilute thrombin time or ecarin-based assay measures dabigatran.

Anti-Xa results are quantitative only against the drug's own calibrator. A rivaroxaban-calibrated anti-Xa assay is the correct test.

The PT gives a variable, reagent-dependent response to direct oral anticoagulants and cannot quantify concentration.

Review Anticoagulant measurement

Use it

Read the case evidence, then make each decision. The step is complete without it.

  • A woman with metastatic adenocarcinoma and new sepsis (MRN 0083517) has a coagulation and platelet panel ordered from the intensive care unit.
  • She has no history of a bleeding or platelet disorder.
  • She was started on prophylactic heparin 3 days ago.
TestResultPreviousReference intervalFlag
Platelet count38 × 10³/µL Low3 days ago: 165 × 10³/µL165 × 10³/µL3 days ago150–450 × 10³/µL150–450Low
PT17.2 s High3 days ago: 12.9 s12.9 s3 days ago11.5–14.5 s11.5–14.5High
Fibrinogen92 mg/dL Low3 days ago: 310 mg/dL310 mg/dL3 days ago200–400 mg/dL200–400Low
D-dimer9 × ULN High<1 × ULN × ULN<1 × ULNHigh

Specimen: H 4, L 6, I 2. Citrate plasma and EDTA whole blood, both correctly filled.

Decision 1 of 3

How do you interpret this pattern?

Platelets, PT, and fibrinogen have all moved in the direction DIC produces, over 3 days, with sepsis as a compatible trigger. This panel has more than one abnormal result.

Read a raised D-dimer alone as DIC

D-dimer rises with inflammation, surgery, trauma, pregnancy, cancer, and age. DIC needs a compatible trigger with falling platelets, a lengthening PT, raised D-dimer, and falling fibrinogen, scored and trended with the ISTH overt-DIC score. A single raised D-dimer does not meet these criteria.

Sepsis is a recognized DIC trigger. Platelets fell from 165 to 38 × 10³/µL, the PT lengthened, D-dimer rose to 9 times the upper limit of normal, and fibrinogen fell from 310 to 92 mg/dL, the combination the DIC score is designed to detect.

The timing is early for HIT, which commonly begins 5 to 10 days after a new exposure, and the prolonged PT and falling fibrinogen do not fit HIT as the only process.

Review Disseminated intravascular coagulation

Decision 2 of 3

The team asks whether the low platelet count could also be heparin-induced thrombocytopenia (HIT). What do you tell them?

The timing here, 3 days after a new heparin exposure, together with the DIC-compatible pattern already present, is scored with the other 4Ts elements before a PF4-heparin immunoassay is ordered.

Testing without regard to pretest probability, when the timing and the rest of the picture already point elsewhere, risks a false-positive result being acted on as HIT.

HIT can begin within 3 days after recent prior heparin exposure, so timing alone does not rule it out. The 4Ts score considers the timing together with the rest of the picture.

Review Thrombophilia and heparin-induced thrombocytopenia

Decision 3 of 3

A repeat panel 6 hours later shows the platelet count and fibrinogen both falling further, with the D-dimer still high. What does this trend add?

In consumptive disease, the direction of serial results gives more information than a single value. A worsening trend strengthens the pattern beyond what one panel shows.

Read a raised D-dimer alone as DIC

D-dimer rises with inflammation, surgery, trauma, pregnancy, cancer, and age. DIC needs a compatible trigger with falling platelets, a lengthening PT, raised D-dimer, and falling fibrinogen, scored and trended with the ISTH overt-DIC score. A single raised D-dimer does not meet these criteria.

A falling platelet count and fibrinogen over time, with a persistently high D-dimer, show active, ongoing consumption. The score is reassessed with the trend in view.

A high, unchanged D-dimer alongside worsening platelets and fibrinogen does not show resolution. The falling platelets and fibrinogen are the more informative trend here.

Review Disseminated intravascular coagulation

The repeat panel showed platelets and fibrinogen both falling, with a high D-dimer and a lengthening PT, in a patient with sepsis as a compatible trigger. This combination is the pattern the DIC score is designed to detect.

For reference

Sources checked