202412142019
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Tags: Haematology
von Willebrand disease
Von Willebrand factor is a large glycoprotein required for platelet adhesion at the site of tissue injury (exposed sub-endothelium) and to stabilise Factor VIII (FVIII)
VWF is synthesized in bone megakaryocytes and vascular endothelium and stored in Weibel–Palade bodies in the endothelial cells
Von Willebrand disease (VWD), the most frequent autosomal inherited bleeding disorder, is caused by quantitative or qualitative defects of vWF
As a consequence, in addition to the defect of VWF, also FVIII, the protein deficient in haemophilia A, may be variably reduced in VWD patients
estimated prevalence 1%
clinically significant disease 1 in 10,000
Quantitative deficiency of VWF
- Type 1 Partial quantitative deficiency of VWF
- mildest
- ↓ synthesis or ↑ clearance (Type 1C)
- Type 3 Virtually complete deficiency of VWF (& ↓↓ F8 )
- rare
- clinically most severe
- Allo-antibody formation occurs in 10–15% of type 3 VWD
Qualitative deficiency of VWF = Type 2
- Type 2A
- ↓ platelet-dependent function a/w absence of high- and intermediate-molecular weight VWF multimers
- Type 2B
- ↑ affinity for platelet GPIb
- plt-vWF complexes cleared by ADAMTS13 → ↓ vWF & ↓ plt
- vs platelet type : abnormality lies in plt
- ↑ affinity for platelet GPIb
- Type 2M
- ↓ platelet-dependent function not caused by the absence of high-molecular weight VWF multimers
- "M" ∵ multimer assembly unaffected
- Type 2N
- markedly ↓ affinity for factor VIII
- (vWF ↓ F8 T1/2)
- ∴ ↓ F8 levels
- "N" = Normandy, where it's first discovered
- differentiated from haemophilia A by:
- autosomal recessive inheritence
- genetic studies
- markedly ↓ affinity for factor VIII
also a group of patients who have a bleeding history and milder reductions in VWF activity (0.3–0.5 IU/ml). Recently, these patients have been reclassified as having ‘low VWF’, a risk factor for bleeding, but additional causes of bleeding should be sought
| Type | Effect | Inheritance | Bleeding propensity | Responsive to desmopressin? | Other therapeutic options | CNB |
|---|---|---|---|---|---|---|
| 1 | Partial quantitative deficiency | Autosomal dominant | Mild to moderate | Most | TXA Plasma-derived VWF concentrates (not in mild Type 1) |
Yes, if normal VWF levels achieved |
| 2A | Selective qualitative deficiency with decreased VWF function as a result of loss of high-molecular-weight multimers | Usually autosomal dominant | Variable, usually moderate | Variable, usually inadequate functional response | VWF-containing concentrates TXA |
No |
| 2B | Qualitative deficiency with increased platelet adhesion; can cause thrombocytopenia | Autosomal dominant | Variable, usually moderate | May worsen thrombocytopenia—caution with use | VWF-containing concentrates Platelet transfusion |
No |
| 2M | Qualitative deficiency with decreased VWF-dependent platelet adhesion | Autosomal dominant | Variable, usually moderate | Variable, usually inadequate functional response | VWF-containing concentrates TXA |
No |
| 2N | Decreased binding to FVIII | Autosomal recessive | Variable, usually mild/moderate | Variable | VWF-containing concentrates TXA |
No |
| 3 | Complete quantitative deficiency | Autosomal recessive | Severe | No | VWF-containing concentrates Platelet transfusion TXA |
No |
treatment of VWD requires the correction of the dual haemostatic defect (low FVIII and low/abnormal VWF).
These goals can be achieved by increasing plasma concentrations of these factors through their release from endothelial cells with desmopressin (DDAVP) or by using replacement therapy with human plasma-derived (pd) low-purity VWF/FVIII concentrates or a high-purity VWF product.
Lab test
↓ plt (usually mild ~100-140) if Type 2B
↑ aPTT ∝ ↓ F8 activity
PT normal
microcytic anaemia if IDA
vWF antigen (vWF:Ag): quantitative measurement of vWF protein level
- not imply Fx activity
- IU/dL = %
plt dependent vWF activity e.g. vWF:RCo - assess ability of vWF to bind to plt
Factor VIII activity
Test may be affected by acute illness (vWF & F8 are acute phase reactants), pregnancy, oestrogen exposure (↑ vWF)
derived ratios:
- plt dependent vWF activity to vWF:Ag → Type 2
- normally >0.7 (or close to 1)
- not applicable to Type 3 as levels too low
- F8 activity to vWF:Ag
- Type 2N
Treatment
DDAVP
DDAVP response is mainly dependent on genotype and phenotype
a test-dose infusion at the time of diagnosis is recommended to establish the pattern of response and its duration
Progressive reduced response to DDAVP can be observed due to =depletion= of VWF/FVIII from the storages (tachyphylaxis) after repeated treatments (usually >3 over 24 hours)
The risk of hyponatremia is remote when using a single dose in adults but caution should be used in pregnancy (PET & Oxytocin use further ↑ risks), and fluid restriction is advisable when further dose(s) is required along with monitoring of urinary output and serum electrolytes.
Fluid intake should be restricted to 1 litre for 24 hours following DDAVP administration to prevent maternal hyponatraemia.
If additional fluid is required, electrolytes should be monitored.
theoretical risk of placental insufficiency caused by vasoconstriction, and desmopressin should be avoided in PET
DDAVP is usually effective in patients with type 1 VWD and baseline VWF and FVIII levels ≥10 IU/dL
variable responses are observed in type 2 VWD patients
In type 2B, DDAVP is generally contraindicated ∵ transient appearance or aggravation of thrombocytopenia leading to ↑ risk of bleeding
Type 3 VWD → unresponsive
vWF/FVIII concentrates
| Product | Manufacturer | Purification | Viral inactivation | VWF:RCo/Ag# (Ratio) |
VWF:RCo/FVIII# (Ratio) |
|---|---|---|---|---|---|
| Alphanate | Grifols | Heparin ligand chromatography | S/D + dry heat (80°C, 72 h) | 0.47 ± 0.1 | 0.91 ± 0.2 |
| Factor 8Y | BioProducts Laboratory | Heparin/glycine precipitation | Dry heat (80°C, 72 h) | 0.29 | 0.81 |
| Fanhdi | Grifols | Heparin ligand chromatography | S/D + dry heat (80°C, 72 h) | 0.47 ± 0.1 | 1.04 ± 0.1 |
| Haemate P/Humate | CSL Behring | Multiple precipitation | Pasteurisation (60°C, 10 h) | 0.59 ± 0.1 | 2.45 ± 0.3 |
| Talate | Shire | Ion exchange chromatography | S/D + vapour heat (60°C, 10 h) | 0.47 | 1.1 |
| Wilate | Octapharma | Ion exchange + size exclusion chromatography | S/D + dry heat (100°C, 2 h) | — | 0.9 |
| Wilfactin | LFB | Ion exchange + affinity | S/D, 35 nm filtration, dry heat (80°C, 72 h) | ≈0.95 | ≈50 |
| VonVendi | Shire | Chinese Hamster Ovary (CHO) cell line co-expressing the VWF and FVIII genes, in absence of any animal or other human plasma proteins; purified by immune-affinity chromatography | None | 1.16 ± 0.25 | >100 |
Obstetric considerations
Pregnancy is considered as a hypercoagulable state ∵ because several hemostatic factors increase throughout
- Factor VII,
- factor X,
- fibrinogen
- plasminogen activator inhibitor type 1
free protein S ↓
VWF and FVIII ↑ significantly during pregnancy in normal women reaching the greatest level during the 3rd trimester, with levels far > 100 U/dL by the time of parturition.
Whether or not women with VWD are at ↑ risk of spontaneous abortion is unclear from the literature
A progressive ↑ of FVIII and VWF occurs in most women w/ type 1 VWD, the partial quantitative deficiency of the disorder, with levels reaching >50 U/dL in the 3rd trimester
In general, women with levels at baseline of VWF and FVIII >30 U/dL, suggesting type 1 VWD, usually have a high likelihood to achieve normal levels at the end of pregnancy
Women with basal levels <20 U/dL usually have a lesser increase since most of these women carry DNA variants associated with increased VWF clearance or decreased synthesis and secretion or are compound heterozygous for different VWF variants which prevent the achievement of satisfactory hemostatic levels
Ideally, the results of a test-infusion with DDAVP should be available before pregnancy for every woman with VWD and basal level of FVIII and VWF <30 U/dL
VWD patients should be monitored for VWF:RCo and FVIII:C at least once during the 3rd trimester of pregnancy
The risk of bleeding is minimal when FVIII:C and VWF:RCo levels w/o treatment during pregnancy are ≥50 U/dL
risk of bleeding is highest in those who do not self-correct, even if treated
RCOG advise assessment of plasma VWF levels at booking, third trimester, and prior to any invasive procedures
ACOG favoring third trimester assessment to facilitate delivery planning
proposed definition of PPH in vWD:
Primary postpartum hemorrhage (PPH) includes
- blood loss ≥1000 mL w/i 24 hours of birth, or
- any blood loss with the potential to produce hemodynamic instability.
Of note, once blood loss exceeds 500 mL in a vaginal birth, early intervention with measures known to reduce PPH (eg, uterotonics, tranexamic acid) should be considered.
Secondary PPH includes blood loss that is heavier than normal lochial loss between 24h & 6wks postpartum and
- Necessitates medical review or intervention between 24 hours and 6 weeks postpartum, or
- Lasts beyond 6 weeks after childbirth
SA / EA
Central neuraxial blocks can be offered in Type 1 VWD, in which concentrations of VWF activity and FVIII:C are above 0.5 IU/ml with a normal coagulation screen and platelet count
In Types 2 and 3 VWD, UK guidance advises against the use of CNB, even after VWF replacement therapy.
This is because the achievement of normal laboratory measurements of VWF activity does not usually equate to restoration of normal haemostasis in these patients
As VWF concentrations decrease early in the postpartum period, an epidural catheter should be removed soon after delivery or repeat treatment considered before removal
TXA
Oral TXA should be started at the onset of labour, or administered intravenously before Caesarean section and continued in the postpartum period
A limited amount of TXA (∼1%) may be secreted in breast milk, but this is not considered likely to produce an antifibrinolytic effect in the infant
Type 1
Use of non‐pregnant reference ranges in this clinical context is fraught as plasma VWF levels in pregnant women with type 1 VWD remain consistently lower than their healthy pregnant peers and bleeding may still occur at delivery
In type 1 VWD, pregnant women with FVIII:C and/or VWF levels lower than 30 U/dL at time of parturition, the administration of desmopressin after umbilical clamping and for 3-4 days thereafter is required especially when midline episiotomy is required.
The IV route elicits the same increase as that of the SC one, but the time to peak is generally shorter.
However, monitoring FVIII and VWF levels is advisable, especially when repeated doses are given
Monitoring of urinary output and fluid restriction are necessary to avoid the risk of hyponatremia
alternative approaches using VWF/FVIII concentrates are also used in some Countries especially when close surveillance of the patient is not easily available. In this case, 40-60 IU/kg VWF is administered during the late stage of labour and repeated once daily for at least 3 days, followed by oral TXA for a week.
Other variants
2A
Type 2A VWD is characterised by
- lack of high-molecular weight multimers
- abnormal VWF:RCo/VWF:Ag (<0.6)
During pregnancy, multimer abnormalities usually do not correct and VWF:RCo remains markedly reduced. However, a significant increase of FVIII and VWF:Ag may occur
These patients usually require treatment with FVIII/VWF concentrates
2B (DDAVP C/I)
Worsening of pre-existing thrombocytopenia is the most important change observed in type 2B VWD women during pregnancy because ↑ release of abnormal multimers with enhanced affinity for glycoprotein Ib on platelet surface occurs.
However, its severity is strongly dependent on the specific amino acid change in the A1 domain of VWF responsible for the patient's disease, with some DNA variants resulting in normal platelet counts (eg c.3797C>T, p.Pro1266Leu) while others are associated with severe thrombocytopenia (eg c.3922C>T, p.Arg1308Cys and c.3946G>A, p.Met1316Val).
Regardless of the DNA variant, or if it is not known, platelet count should be also closely monitored during pregnancy in women with this type
In some women with platelet count <30 000/µL, platelet transfusion has been used, despite the fact that pseudo-thrombocytopenia is partly responsible for platelet lowering as assessed by the presence of platelet clumps on peripheral blood smear
2M
Women with type 2M VWD often show a significant correction of FVIII and VWF:Ag, while VWF:RCo does not reach levels of 50 U/dL.
This is similar to the pattern observed after desmopressin in these patients and means that factor replacement should be used
2N
In type 2N VWD, normalisation of FVIII, which is more reduced compared to VWF in this type, usually occurs during pregnancy in women heterozygous or homozygous for the most frequent DNA variant and amino acid change responsible for this type (c.2561G>A, p.Arg854Gln), similar to what happens after desmopressin
the results of a desmopressin trial before pregnancy are helpful to predict its usefulness at parturition.
in unresponsive women, during labour and before epidural anaesthesia, 50 IU/kg of VWF should be administered, followed by 30-40 IU/kg/daily for at least 3 days.
Daily monitoring of FVIII and VWF activity is recommended during the same period. Oral tranexamic acid is advised (15-25 mg/kg) up to 10-15 days.
Type 3
Women with type 3 VWD typically do not show any increase of FVIII and VWF during pregnancy because their endothelial VWF stores are lacking. Thus, VWF/FVIII concentrates may be required during pregnancy to control intermittent vaginal bleeding and at delivery or for caesarean section
Replacement therapy is as suggested above, but it usually should be prolonged up to 5-7 days to maintain FVIII:C (and possibly VWF) level >50 U/dL
Usual thrombo-prophylactic treatment with LMWH should be considered in patients at high risk of venous thrombosis during replacement therapy for caesarean section, especially if high FVIII levels are anticipated by using replacement treatment
Post partum
Factor VIII and VWF fall to baseline levels soon after delivery (by 3 wks post partum)
oral antifibrinolytic agents (eg TXA 1 g every 8 hours up to 2 weeks) can be used during this period to prevent delayed PPH due to heavy lochia.
remove EA catheter quickly (or repeat treatment)
Tranexamic acid appears to decrease the risk of delayed PPH and appears to be safe during lactation.
References
Pregnancy and delivery in women with von Willebrand disease - Castaman - 2019 - European Journal of Haematology - Wiley Online Library
Pregnancy and Delivery in Women With Von Willebrand Disease
Haemostatic Disorders in Pregnancy - BJA Ed
Haemostatic disorders in pregnancy - ScienceDirect