When an Abnormal Test Is Not Enough

When an Abnormal Test Is Not Enough

Reconsidering the diagnosis of von Willebrand disease during pregnancy

By William C. Aird, MD

Case Presentation

A 32-year-old woman is admitted in early labor with a longstanding diagnosis of type 2 von Willebrand disease (VWD).

She was originally diagnosed after prolonged bleeding following a periodontal procedure many years earlier. At that time, laboratory testing reportedly showed:

She was told she had type 2 VWD and advised to use aminocaproic acid for future bleeding episodes.

Despite this diagnosis, she reports:

• no childhood bleeding
• no excessive bruising
• no heavy menstrual bleeding
• no family history of a bleeding disorder
• one prior cesarean delivery without excessive bleeding

She is now admitted for her second delivery.

Which feature of this patient’s history raises the greatest uncertainty about the diagnosis of inherited von Willebrand disease?

Explanation

A diagnosis of inherited VWD requires integration of both laboratory findings and bleeding phenotype.

Although this patient experienced prolonged bleeding after a periodontal procedure, she has:

• no childhood bleeding history
• no menorrhagia
• no family history
• a previous uncomplicated cesarean delivery

A mild laboratory abnormality in the absence of a convincing bleeding phenotype should prompt reconsideration of the diagnosis rather than automatic acceptance of an existing disease label.

Laboratory Reassessment

During the third trimester, repeat hemostatic testing demonstrates:

Multimer analysis shows only a minimal decrease in high-molecular-weight multimers, without abnormal banding.

These findings are consistent with a mild qualitative VWF abnormality but do not establish clinically significant von Willebrand disease.

How should the reduced platelet-dependent VWF activity-to-antigen ratio be interpreted?

Explanation

A reduced activity-to-antigen ratio suggests qualitative dysfunction of VWF.

However, diagnosis should not rely on the ratio alone.

Equally important are:

• the absolute platelet-dependent VWF activity
• the patient’s bleeding history
• family history
• the clinical setting

During pregnancy, VWF antigen and factor VIII normally increase substantially. Although the activity-to-antigen ratio remains relatively low in this patient, her absolute platelet-dependent VWF activity is within the normal range and her clinical bleeding history is remarkably mild.

Clinical Decision

Because she carries a diagnosis of type 2 VWD, the obstetric team asks hematology how postpartum hemorrhage should be managed.

A plan is developed:

• routine obstetric management
• intravenous tranexamic acid if postpartum bleeding develops
• VWF replacement only if bleeding persists despite standard measures

Desmopressin is not recommended because of the presumed qualitative VWF defect.

Does Every Qualitative VWF Abnormality Constitute VWD?

Unlike type 1 VWD, which is defined primarily by reduced VWF quantity, type 2 VWD is defined by disproportionately impaired VWF function. A patient may therefore have a genuine qualitative VWF defect even when the absolute platelet-dependent VWF activity is above 30 IU/dL.

That laboratory pattern establishes evidence of abnormal VWF function; it does not, by itself, establish clinically significant von Willebrand disease.

The diagnosis depends on whether the abnormality is reproducible, biologically coherent, and clinically meaningful. Interpretation should incorporate:

• bleeding history
• family history
• nonpregnant baseline VWF levels
• activity-to-antigen ratio
• multimer distribution
• collagen-binding results
• subtype-specific testing such as RIPA or VWF:FVIII binding
• genetic findings, when informative

The central question is therefore not:

“Is the assay abnormal?”

It is:

“Does this abnormality meaningfully increase bleeding risk and justify a lifelong diagnosis of von Willebrand disease?”

For this patient, pregnancy further complicates interpretation because it raises VWF antigen and activity. Her nonpregnant activity could be lower, but that must be demonstrated rather than assumed.

Why is immediate prophylactic VWF replacement not recommended before delivery?

Explanation

Management should be individualized.

Although this patient carries a historical diagnosis of type 2 VWD, she has:

• normal pregnancy-adjusted VWF activity
• markedly elevated factor VIII activity
• no significant bleeding phenotype
• no prior obstetric bleeding

These features favor observation with a clear treatment plan should postpartum hemorrhage occur rather than routine prophylactic factor replacement.

Clinical Course

The patient delivers without postpartum hemorrhage.

Neither tranexamic acid nor VWF replacement is required.

She recovers uneventfully.

Following delivery, her hematologist revisits the original diagnosis.

Although the reduced activity-to-antigen ratio may reflect a mild qualitative abnormality of VWF, the available evidence does not clearly demonstrate clinically significant von Willebrand disease.

Which statement best summarizes the most appropriate conclusion?

Explanation

Supportive therapies such as VWF-containing concentrates, desmopressin, antifibrinolytics, or intravenous immunoglobulin may temporarily improve hemostasis in selected patients.

However, durable control of acquired VWS often requires treatment of the underlying disorder responsible for the abnormal VWF metabolism.

In lymphoplasmacytic disorders, successful treatment of the clone may restore normal VWF levels and reduce bleeding.

Teaching Points

• A diagnosis of von Willebrand disease requires integration of laboratory findings and bleeding phenotype.
• A reduced platelet-dependent VWF activity-to-antigen ratio suggests qualitative VWF dysfunction but is not diagnostic by itself.
• Pregnancy physiologically increases VWF antigen and factor VIII, which may reduce bleeding risk at delivery.
• Management decisions should be based on the patient’s current bleeding risk rather than a historical diagnostic label alone.
• Clinical judgment includes recognizing when available evidence no longer supports an established diagnosis.

Why This Case Matters

This case highlights an increasingly common challenge in modern hematology. As laboratory testing becomes more sensitive, clinicians encounter patients with measurable abnormalities of VWF biology but little or no clinically important bleeding. Such individuals may have a laboratory phenotype without a clear disease phenotype. The task is not simply to decide whether the assay is abnormal, but whether the abnormality meaningfully increases bleeding risk, changes management, and justifies a lifelong diagnosis. In VWD, as in much of medicine, biology exists on a continuum, whereas diagnostic labels are binary. Expert judgment lies in knowing when the continuum has crossed the threshold into disease.