Von willebrand disease

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"von Willebrand disease"[MeSH Terms] AND management

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Von Willebrand Disease (VWD)

Definition & Epidemiology

Von Willebrand disease is the most common inherited bleeding disorder, affecting approximately 1% of the population, with clinically significant bleeding symptoms in ~1 in 1,000 individuals. Prevalence is consistent across races and ethnicities. It is caused by quantitative or qualitative deficiency of von Willebrand factor (VWF) - a large multimeric plasma glycoprotein essential for normal hemostasis.

Clinical disease is more prevalent in females despite autosomal inheritance, because they face greater hemostatic challenges (menorrhagia occurs in up to 80% of women with VWD).

Goldman-Cecil Medicine, p. 1400-1401
Robbins & Kumar Basic Pathology, p. 430

Structure & Function of VWF

VWF-Factor VIII complex and platelet adhesion at a site of vascular injury

Structure and function of factor VIII-vWF complex (Robbins & Kumar)

VWF has two critical roles in hemostasis:

Platelet adhesion - mediates platelet binding to exposed subendothelial collagen at vascular injury sites via the glycoprotein Ib (GpIb) receptor
Factor VIII carrier - protects factor VIII from premature proteolytic degradation; the VWF-FVIII complex circulates together in plasma

Synthesis and storage:

Produced in endothelial cells and megakaryocytes
Stored in Weibel-Palade bodies (endothelium) and alpha-granules (platelets)
Released by secretagogues: histamine, thrombin, DDAVP
VWF monomers dimerize in the endoplasmic reticulum, then form high-molecular-weight (HMW) multimers in the Golgi via N-terminal disulfide bonds

Multimeric structure is critical: HMW multimers bind collagen and platelets with highest affinity and are most efficient in inducing platelet aggregation under high-shear conditions.

ADAMTS13 (a metalloprotease) cleaves ultralarge VWF multimers released from endothelial cells to generate the spectrum of circulating multimers. Deficiency of ADAMTS13 leads to TTP (distinct from VWD).

Goldman-Cecil Medicine, p. 1405-1413
Tietz Textbook of Laboratory Medicine 7th Ed, p. 3073

Classification and Subtypes

Type	Description	FVIII	VWF:RCo	VWF:Ag	HMW Multimers
1	Quantitative deficiency (most common, ~70-80%)	↓ or N	<30%	<30%	Normal distribution, decreased quantity
2A	Qualitative - loss of HMW multimers (not synthesized)	↓ or N	↓	N to ↓	Absent
2B	Qualitative - "hyperfunctional" HMW multimers rapidly cleared; spontaneous platelet aggregation; mild thrombocytopenia	↓ or N	↓	N to ↓	Absent (↑ RIPA at low dose ristocetin)
2M	Qualitative defect - decreased platelet binding without multimer loss	↓ or N	↓	N to ↓	Normal
2N	Qualitative defect - only in FVIII binding (mimics hemophilia A)	↓↓	Normal	Normal	Normal
3	Near-complete absence of VWF (most severe, autosomal recessive)	↓↓	<3%	<3%	Absent
"Low VWF"	Borderline values, often not true hereditary VWD	N	30-50%	30-50%	Normal

Goldman-Cecil Medicine, Table 59-1

Genetics:

Types 1, 2, 3: autosomal
Type 1: autosomal dominant, reduced quantity of VWF
Type 3: autosomal recessive (homozygous), near-total absence - can cause features resembling hemophilia due to severe FVIII deficiency
The VWF gene spans 178 kb on chromosome 12, comprising 52 exons

Clinical Manifestations

Mucocutaneous bleeding pattern (distinguishes VWD from hemophilias):

Epistaxis
Gum bleeding
Easy bruising
Prolonged bleeding from minor wounds
Menorrhagia (hallmark in women; up to 80% of female patients)
Recurrent gastrointestinal bleeding (especially types 2 and 3)

In rare homozygous (type 3) patients: deep tissue bleeds and hemarthroses can occur due to concomitant severe FVIII deficiency, resembling hemophilia.

Diagnosis

Initial Labs

Test	Purpose
VWF antigen (VWF:Ag)	Quantifies total VWF protein
VWF ristocetin cofactor activity (VWF:RCo)	Assesses functional VWF
Factor VIII activity	Reduced in severe VWD
RCo:Ag ratio	<0.7 suggests qualitative defect (type 2)

Normal plasma VWF: 50-150 IU/dL. Blood group O individuals have ~25% lower levels than group AB.

Supplementary Tests (for type 2 subclassification)

VWF multimer analysis - electrophoresis to assess multimer distribution; required for 2A, 2B, 2M
RIPA (ristocetin-induced platelet aggregation) - abnormal response to low-dose ristocetin (0.5 mg/mL) is diagnostic for type 2B
VWF:FVIII binding assay - low binding capacity diagnoses type 2N (mimics hemophilia A)

Tietz Textbook of Laboratory Medicine 7th Ed, p. 4092-4101

Treatment

1. DDAVP (Desmopressin)

Drug of choice for type 1 VWD and some type 2A/2M patients.

Mechanism: releases VWF from Weibel-Palade bodies, transiently elevating plasma VWF
Routes:
- IV: 0.3 µg/kg in 100 mL normal saline over 20 minutes (max 25-30 µg)
- Intranasal: 300 µg total (or 150 µg per nostril for persons >50 kg)
Contraindicated in type 2B (releases abnormal HMW multimers that worsen thrombocytopenia)
Tachyphylaxis occurs with repeated use; response decreases after 2-3 doses (Weibel-Palade stores deplete)
Test dose recommended before elective use

2. VWF Concentrate (Factor Replacement)

For major surgery, severe bleeds, type 3, or DDAVP-unresponsive patients:

Initial dose: 40-60 RCo units/kg; Maintenance: 20-40 RCo units/kg every 8-24 hr
Monitor trough and peak FVIII and RCo daily
Targets: troughs >50% RCo; peaks <200% RCo, <250% FVIII

3. Antifibrinolytics

Tranexamic acid (oral 25 mg/kg three times daily or IV 15 mg/kg three times daily):

Useful adjunct for mucosal bleeding, dental procedures (7-10 day course)
Minimal thrombotic risk even in high-risk populations
Avoid with significant hematuria (risk of clot retention and urinary obstruction)

4. Hormonal therapy

Combined oral contraceptives for menorrhagia in women.

Acquired von Willebrand Syndrome

VWD can be acquired (not inherited), with no personal or family history of lifelong bleeding. Causes include:

Autoantibodies - lymphoproliferative disorders, myeloma, MGUS
VWF adsorption onto cells - Wilms tumor (expressing GpIb), myeloproliferative disorders with elevated platelets
Increased shear-force proteolysis - aortic stenosis, LVAD, congenital heart disease (Heyde syndrome)
Hypothyroidism - decreased VWF synthesis/secretion

Tietz Textbook of Laboratory Medicine 7th Ed, p. 4104-4118

Key Distinguishing Points

Feature	VWD	Hemophilia A
Pattern	Mucocutaneous	Deep tissue/hemarthroses
Inheritance	Autosomal	X-linked recessive
Sex affected	Both (more symptomatic in females)	Predominantly males
vWF	Reduced or dysfunctional	Normal
FVIII	Normal to mildly reduced	Markedly reduced
Platelet count	Usually normal (low in type 2B)	Normal
BT/PFA-100	Prolonged	Normal

Sources: Goldman-Cecil Medicine (International Edition), p. 1400-1575 | Robbins & Kumar Basic Pathology, p. 430-431 | Tietz Textbook of Laboratory Medicine 7th Ed, p. 3073-4140

FNAC

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Fine Needle Aspiration Cytology (FNAC)

Definition & Overview

FNAC is a minimally invasive diagnostic technique that uses a thin needle (typically 22-27 gauge) to aspirate cells from a mass lesion for cytological examination. It is widely available, simple, relatively safe, and can be performed as an outpatient procedure with little patient discomfort.

Bailey and Love's Short Practice of Surgery 28th Ed
Cummings Otolaryngology Head & Neck Surgery

Principle of FNAC

The needle is inserted into the target lesion, and negative pressure (suction) is applied via a syringe to aspirate cells. The aspirated material is then smeared onto glass slides, fixed (wet or air-dried), and stained for cytological analysis. It yields individual cells and cell clusters but not tissue architecture - this is the key limitation distinguishing it from core needle biopsy and histopathology.

Technique

Equipment:

22-25 gauge needle (fine needle), 10-20 mL syringe, syringe holder/pistol grip
Glass slides, fixative (95% ethanol for Papanicolaou stain; air-dry for Giemsa/Diff-Quik)

Steps:

Palpate and immobilize the lesion with the non-dominant hand
Clean the skin with antiseptic; local anaesthesia usually not required for superficial lesions
Insert the needle into the lesion
Apply suction by withdrawing the syringe plunger (negative pressure)
Make multiple passes through the lesion while maintaining suction (fan-shaped movements)
Release suction before withdrawing the needle (to prevent aspirate entering the barrel)
Express material onto glass slides and smear immediately
Fix and stain

Ultrasound guidance is strongly recommended - it improves sensitivity, specificity, and accuracy, particularly for non-palpable, deep, or complex lesions.

Non-aspiration (capillary) technique - used for hypervascular lesions (e.g., thyroid) to reduce blood contamination; relies on capillary action alone without syringe suction.

Advantages

Advantage	Detail
Minimally invasive	No incision required; outpatient procedure
Rapid results	Same-day diagnosis possible with on-site evaluation
High accuracy	Sensitivity 80-99%, specificity 97-100% depending on site
Cost-effective	Significantly reduces unnecessary surgeries
Safe	Very low complication rate vs. larger bore biopsies
Diagnostic AND therapeutic	Can drain cysts (breast, thyroid) while sampling

Limitations

Cannot assess tissue architecture - cannot distinguish invasive from in-situ cancer, or follicular adenoma from follicular carcinoma (requires capsular/vascular invasion assessment)
Operator dependent - accuracy varies greatly with aspirator skill and cytopathologist experience
Sampling error - inadequate/non-diagnostic rate ~5-15%; false-negative rate 1-6%
Ancillary studies limited - lymphoma and high-grade malignancies require flow cytometry and immunohistochemistry, which need core needle biopsy for adequate tissue
Non-diagnostic results should never be interpreted as negative for malignancy
Mulholland and Greenfield's Surgery 7th Ed, p. 3883
Bailey and Love's 28th Ed

Applications by Site

1. Thyroid Nodules (Primary indication)

FNAC is the single most accurate and cost-effective investigative procedure for thyroid nodules. It has:

Decreased the number of patients requiring surgery by 20-75%
Nearly tripled the yield of carcinomas in surgical specimens
Sensitivity >80%, specificity >90%

Indications for FNA (based on ultrasound features and size):

High/intermediate suspicion features (solid hypoechoic with microcalcifications): nodule ≥1 cm
Low suspicion features: nodule ≥1.5 cm
Very low suspicion (spongiform/partially cystic): nodule ≥2.0 cm
Purely cystic nodules: FNA generally not recommended diagnostically (can be done therapeutically)
18FDG-PET hypermetabolic nodules: biopsy if ≥1 cm (~35% malignancy risk)

Key limitation: Follicular neoplasm vs. follicular carcinoma CANNOT be differentiated by FNAC - requires histological evidence of capsular or vascular invasion.

Bethesda System for Reporting Thyroid Cytopathology (BSRTC) - 2023 (3rd edition):

Bethesda Category	Description	Malignancy Risk	Management
I	Nondiagnostic / Unsatisfactory	Variable	Repeat US-guided FNA
II	Benign	~3%	Clinical follow-up
III	Atypia of Undetermined Significance (AUS)	10-40%	Repeat FNA or molecular testing
IV	Follicular Neoplasm (FN)	20-40%	Lobectomy vs. molecular testing
V	Suspicious for Malignancy	~75%	Near-total thyroidectomy or lobectomy
VI	Malignant	~99% (98% PTC)	Surgery

Sabiston Textbook of Surgery, p. 1505-1506
K.J. Lee's Essential Otolaryngology
Goldman-Cecil Medicine

2. Salivary Gland Lesions

Performance: Sensitivity 85.5-99%, specificity 96.3-100%. Accuracy is higher for benign lesions. False-negative for malignancy occurs in up to 5% of cases.

Milan System for Reporting Salivary Gland Cytopathology (MSRSGP):

Category	Risk of Malignancy	Management
I Non-diagnostic	25%	Repeat FNAC / radiological correlation
II Non-neoplastic	10%	Clinical follow-up
III AUS (Atypia of Undetermined Significance)	20%	Repeat FNAC or surgery
IVA Benign Neoplasm	<5%	Conservative surgery or follow-up
IVB SUMP (Salivary gland neoplasm of Uncertain Malignant Potential)	35%	Conservative surgery
V Suspicious for Malignancy	60%	Surgery
VI Malignant	>90%	Surgery (extent per type/grade)

Bailey and Love's 28th Ed, Table 54.4
Cummings Otolaryngology

3. Breast Lesions

FNAC is the least invasive breast biopsy method. Can be done by palpation or image guidance.

Sensitivity 98%, specificity 97% (in experienced hands)
Classic Triple Test (clinical + imaging + FNAC) - all three must agree for definitive benign diagnosis
Limitation: Cannot diagnose invasive cancer (no tissue architecture) - cannot confirm invasion
Currently, high-suspicion lesions are preferred to undergo core needle biopsy for superior histological diagnosis
Simple breast cysts: therapeutic aspiration is a primary indication

4. Head & Neck Lymph Nodes

Evaluation of cervical lymphadenopathy (reactive vs. metastatic vs. lymphoma)
Avoids open biopsy in many cases
With immunohistochemical staining for EBV RNA (EBER), diagnosis of nasopharyngeal carcinoma (NPC) with neck node metastasis can be confirmed
For lymphoma: core needle biopsy preferred over FNAC as flow cytometry and immunohistochemistry require more tissue

5. EUS-FNA (Endoscopic Ultrasound-Guided FNA)

Used for:

Pancreatic masses and cysts
Mediastinal lymph nodes
Submucosal GI lesions
Peri-intestinal masses
Clinical Gastrointestinal Endoscopy 3rd Ed

6. Other Sites

Site	Application
Liver	Focal hepatic lesions
Lung	Peripheral and central masses (CT-guided)
Kidney	Renal masses
Bone	Osteolytic lesions
Soft tissue	Subcutaneous/deep soft tissue masses
Mycetoma	Distinguishes eumycetoma vs. actinomycetoma

Complications

Generally very few and minor:

Local hematoma / bruising - most common
Infection - rare
Pneumothorax - with lung or deep neck FNAC
Tumor seeding along needle track - extremely rare; theoretical concern
Vasovagal syncope
Inadequate sample (5-15%) - not a complication per se but a procedural failure

FNAC vs. Core Needle Biopsy vs. Excision Biopsy

Feature	FNAC	Core Needle Biopsy	Excision Biopsy
Needle size	22-27G (fine)	14-18G (large bore)	Surgical
Yield	Cytology (cells only)	Histology (tissue cores)	Histology (whole specimen)
Tissue architecture	No	Yes	Yes
Invasion assessment	No	Yes	Yes
Ancillary tests (IHC, flow)	Limited	Yes	Yes
Complication risk	Very low	Low-moderate	Higher
Cost	Low	Moderate	High
Best for	Thyroid, salivary, cysts	Breast, lymphoma	Uncertain/failed biopsy

Reporting Systems Summary

Site	Reporting System
Thyroid	Bethesda System (BSRTC) - 6 categories (2023, 3rd ed.)
Salivary Gland	Milan System (MSRSGP) - 6 categories
Breast	B-classification (B1-B5) or ACR BI-RADS correlations
Pancreas	Papanicolaou Society guidelines

Sources: Sabiston Textbook of Surgery (Elsevier) | Bailey & Love's Short Practice of Surgery 28th Ed | Cummings Otolaryngology 7th Ed | Mulholland & Greenfield's Surgery 7th Ed | K.J. Lee's Essential Otolaryngology | Goldman-Cecil Medicine (International Ed)

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