Essentials It is unclear if platelet function differs between preterm and full-term neonates. Platelets from preterm neonates behave differently on VWF compared to full-term neonates. It is unclear whether platelet function differs between preterm and full-term neonates. This is partly because of the large volumes of blood required to perform standard platelet function tests, and the difficulty in obtaining such samples in neonates. Objectives This study was designed to characterize platelet behavior in neonates with a physiologic flow-based assay that quantifies platelet function in microliter volumes of blood under arterial shear.
September Protein Nude massage in virinia deficiency has been very rarely reported in neonates. This is partly because of the large volumes of blood required to perform standard platelet function tests, and the difficulty in obtaining such samples in neonates. Infants with homozygous Protein C deficiency often have significant in utero thrombotic events cerebral or ophthalmic and severe DIC and large vein thromboses. VKDB classically presents inant days of life in breastfed babies who did not receive Von willebrand disease premature infant vitamin K at birth. Haemophilia and Comments.
Avril stocking hat. Investigations
Women Genital wart over VWD are five times more likely to have postpartum hemorrhage excessive bleeding in the mother after delivery. ProLeup. More detailed information for clinicians ordering genomic testing can be found here. Missense variants, infnt in the D3 and A1 domains [ Wi,lebrand et alMillar et alEikenboom et al ], reduce the residence time of VWF in plasma by many fold. Williams Hematology. Bleeding symptoms and laboratory correlation in patients with severe von Willebrand disease. Delayed, secondary postpartum bleeding Von willebrand disease premature infant be a problem. Parvovirus B19 can cause a mild disease fever, rash, aches and pains in adults, but can cause severe, life-threatening anemia in unborn babies. Type 2N VWD. There may be a family history of specific haematological diagnoses, or there may be more general notes about bleeding Von willebrand disease premature infant in the maternal history. Although the autosomal inheritance pattern predicts that both sexes prrmature be equally affected, there is a higher frequency of symptomatic VWD in women because of the hemostatic challenges of menses, pregnancy and delivery [ 3 - 5 ]. Miscarriage There is no evidence that VWD impairs fertility or increases the risk of miscarriage, even in women with severe type 3 disease [ 43354 ]. PLoS Prematuer. Citing Literature. We wi,lebrand use the most recent VWF value during the pregnancy to develop a written birth plan.
There may be a family history of specific haematological diagnoses, or there may be more general notes about bleeding tendencies in the maternal history.
- Use the link below to share a full-text version of this article with your friends and colleagues.
- For women with bleeding disorders including carrier s , pregnancy can be a time of heightened worry and confusion.
- There may be a family history of specific haematological diagnoses, or there may be more general notes about bleeding tendencies in the maternal history.
- It has an autosomal inheritance pattern, so men and women are equally likely to be affected.
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Editor-in-Chief, Dr. Laura Michaelis introduces the The Hematologist print redesign, including a better layout, more modern look, and clearer signposts within. Voxelotor: Changing the Disease by Changing the Conformation. Wilson, Monahan, Little, and Osunkwo discuss a trial that tests voxelotor, a new disease-modifying therapy being considered for sickle cell disease. The Case A year-old woman 28 weeks into her first pregnancy is referred to hematology clinic given a history of von Willebrand disease vWD diagnosed during her teenage years, after presenting with excessive menstrual bleeding requiring oral iron supplementation.
She had taken oral contraceptives until six months prior to this pregnancy with improvement in her bleeding symptoms. She has no family history of vWD and has never had prior surgery or dental extractions. First, it serves as a bridging molecule between platelets and subendothelial collagen exposed during vascular injury. Second, it acts as a chaperone protein for factor VIII, preventing premature degradation and increasing availability at sites of active thrombus formation.
The vast majority of cases are type 1, resulting in mild to moderate reduction of functionally normal vWF. Bleeding severity, however, is variable, and only a fraction of individuals with the disorder present with symptoms of bleeding. The gene encoding vWF is located on chromosome 12, spanning kb over 52 coding exons. During pregnancy, hormonal influences lead to an increase in vWF and clotting factors VII, VIII, and X while anticoagulant factors such as protein S decrease, shifting hemostasis to a procoagulant state to compensate for anticipated hemorrhage during parturition.
This is best conducted with a multidisciplinary team for safest care of the mother and baby. Given the hormonal changes that occur during pregnancy, the diagnosis can be obscured and is ideally made prior to conception. In addition to a complete blood count to evaluate platelet count and standard coagulation studies PT and PTT , recommended screening tests include plasma vWF:Ag, vWF activity with ristocetin cofactor activity being most commonly performed, and the collagen binding assay less readily available , and FVIII activity.
In type 1 vWD, multimers are normal or mildly decreased with normal distribution. Type 2B variant is characterized by gain of function mutations in the GPIb binding site of the vWF protein, causing a conformational change leading to enhanced affinity for GPIb. This can be demonstrated by performing RIPA, a type of platelet aggregation study using platelet-rich plasma PRP to screen for the ability of the patient vWF to bind to platelet GPIb in the presence of a low concentration of ristocetin 0.
With normal vWF protein, aggregation does not occur at ristocetin concentrations below 0. In contrast, type 2B variant is associated with hyper-responsiveness to a low ristocetin concentration. Analytic sensitivity is reported to be more than 99 percent for reported mutations, with results typically available within three weeks.
Thrombocytopenia is frequently seen in patients with Type 2B vWD, occurring in about 40 to 50 percent of cases, and it has been shown to be an independent risk factor for bleeding in such patients. One way to try to distinguish these possibilities is by performing RIPA mixing studies. Antepartum hemorrhage is uncommon, but PPH has been observed in up to The agent therefore, may be a safe option in pregnancy. Furthermore, in type 2B, use of DDAVP can exacerbate thrombocytopenia, leading to an additional risk of bleeding; this agent is contraindicated if a persistent decrease in platelet count has been documented.
Replacement products are needed for type 2B and 3 vWD. In phase III studies, use of rvWF was highly effective in restoring hemostasis, with hemostatic levels achieved within six hours and sustained for up to 72 hours following infusion. Other adjunctive options include antifibrinolytic agents such as tranexamic acid and aminocaproic acid in the postpartum setting. Although they have not been studied specifically in the management of PPH, retrospective studies have shown reduction in rates of PPH when used for up to three weeks following discharge.
Multimer analysis showed loss of high-molecular weight multimers. RIPA testing was performed Table 2 , showing typical aggregation findings observed in type 2B vWD, including the hyper-responsiveness to a low ristocetin concentration see Table 2 results in red type for patient PRP aggregation percentage with ristocetin concentrations of 0.
The delivery plan includes administration of vWF concentrates at time of delivery, possible platelet transfusion, and oral tranexamic acid after discharge.
A new Compendium providing updated clinical information to "Ask the Hematologist" articles published in The Hematologist from to is now available. Phone Fax Ask the Hematologist. Home Columns Ask the Hematologist. Table 1. Table 2. Ask the Hematologist Compendium A new Compendium providing updated clinical information to "Ask the Hematologist" articles published in The Hematologist from to is now available.
Learn more. Decreased vWF-dependent platelet adhesion with selective deficiency of high-molecular-weight multimers. Decreased vWF-dependent platelet adhesion without selective deficiency of high-molecular-weight multimers.
Low or normal. Nomenclature Changes in nomenclature: von Willebrand's disease has been replaced by von Willebrand disease. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. An international registry-based study. Essentially normal. Richards, M. Diagnosis during pregnancy may be masked by an increase in FVIII levels to the normal range in milder cases.
Von willebrand disease premature infant. Bleeding during pregnancy
Childbirth and the postpartum period remains a hemostatic challenge, however. Even when pregnant women with VWD have levels of VWF that are considered normal for women who are not pregnant, they still have more postpartum bleeding than patients without VWD. Why should this be, when the VWF levels appear to be sufficient to provide good hemostasis? One possibility is that in the case of postpartum bleeding, a higher level of VWF than normal nonpregnant levels is required to achieve hemostasis.
Another possibility is that our laboratory tests do not measure all the properties of VWF that play a role in hemostasis. More research is required. Regardless of the cause, however, the hospital staff must be aware that these patients are at increased risk for postpartum hemorrhage. Another concern for women with VWD is that their iron levels may have been slightly low before pregnancy, so they are more likely to become anemic during pregnancy.
An important step is putting all these team members in place early on: a hematologist, a high-risk obstetrician or one who is experienced in managing patients with a bleeding disorder, an anesthesiologist, and a neonatologist.
The hospital should also have a pediatric hematologist available in case one is needed for the newborn. Knowing the VWF levels will also inform treatment if a bleeding complication develops, so we want to have a recent value. We also use the most recent VWF value during the pregnancy to develop a written birth plan.
The birth plan describes the bleeding prophylaxis that may be needed for the delivery and postpartum period, and the steps to take to treat episodes of bleeding.
Everyone on the team receives a copy of this plan. The delivery should take place in a hospital where all is available that is required to manage potential complications if significant bleeding develops. This encompasses the expertise of an obstetrician, anesthesiologist, and neonatologist, along with access to resources such as a pharmacy and a blood bank. The facility must be able to care for a bleeding emergency in either the mother or the neonate.
Some women wish to have a home birth, but this is contraindicated for patients with a bleeding disorder. As I mentioned earlier, women with VWD have the option of neuraxial anesthesia—either epidural or spinal—if their VWF levels are normal or corrected with treatment.
We recommend avoiding instrumentation when possible, but the route of delivery, vaginal or cesarean, is dictated by obstetric considerations alone. Women with type 1 VWD typically do not require bleeding prophylaxis at the time of delivery, but we use an antifibrinolytic agent—usually tranexamic acid but sometimes aminocaproic acid—to provide postpartum prophylaxis. A longer period of prophylaxis is required after a cesarean delivery than after a vaginal delivery.
It is important to remain focused on the mother after delivery because it is easy to underestimate excessive postpartum bleeding or dismiss it as normal.
If the patient tells a nurse about bleeding in the postpartum period, we want the nurse to inform the obstetrician and the hematologist. We also want the patient to call her physician about any bleeding after she has returned home. Good communication is essential. There is no evidence that we should change, for example, the route of delivery depending on whether the child is affected.
We do recommend avoiding instrumentation that could cause trauma to the mother or baby. However, most of the babies do very well and do not require testing for VWD until later in childhood. The babies who must be evaluated immediately by a pediatric hematologist are those who have signs of bleeding, are premature, or require a procedure. Complex changes in von Willebrand factor-associated parameters are acquired during uncomplicated pregnancy.
PLoS One. Bleeding events and other complications during pregnancy and childbirth in women with von Willebrand disease.
J Thromb Haemost. Postpartum von Willebrand factor levels in women with and without von Willebrand disease and implications for prophylaxis. Johnsen J, Ginsburg D. Williams Hematology. Chapter How I treat type 2B von Willebrand disease [published online January 29, ]. Reynen E, James P. Von Willebrand disease and pregnancy: a review of evidence and expert opinion.
Semin Thromb Hemost. Primary postpartum haemorrhage in women with von Willebrand disease or carriership of haemophilia despite specialised care: a retrospective survey. Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:. Offspring of a proband. Other family members. The risk to other family members depends on the status of the proband 's parents: if a parent is affected , his or her family members may be at risk.
The offspring of an individual with autosomal recessive VWD are obligate heterozygotes carriers for a pathogenic variant in VWF. Carrier testing for at-risk relatives requires prior identification of the VWF pathogenic variant s in the family. See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment. Considerations in families with an apparent de novo pathogenic variant.
When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo.
However, non-medical explanations including alternate paternity or maternity e. DNA banking is the storage of DNA typically extracted from white blood cells for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.
Once the VWF pathogenic variant s have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for von Willebrand disease are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis.
While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here. Gene structure. For a detailed summary of gene and protein information, see Table A , Gene. Domain structure and exons encoding each VWF domain are shown in Figure 3. Bold horizontal lines indicate the approximate position of exons where pathogenic variants are most prevalent; thinner lines indicate exons with more Pathogenic variants.
The types of variants most commonly associated with VWD subtypes are described here. Partial quantitative deficiency in type 1 VWD is mostly associated with missense variants. In a recent Spanish study of individuals with VWD, Variants associated with type 1 include:. Missense variants, predominantly in the D3 and A1 domains [ Haberichter et al , Millar et al , Eikenboom et al ], reduce the residence time of VWF in plasma by many fold.
The so-called "Vicenza" variant, p. ArgHis , is the best characterized and the most common of these pathogenic variants. Such pathogenic variants have been referred to as type 1 clearance 1C [ Haberichter et al ].
Type 2 VWD. Most pathogenic variants seen in types 2A and 2M and all pathogenic missense variants in type 2B are located in exon Severe quantitative deficiency in type 3 VWD typically results from homozygosity or compound heterozygosity for null alleles, but also a small proportion of missense variants.
Out-of-frame deletions predominate in type 3 VWD, while in-frame deletions of up to nine exons have also been reported in types 1 and 2 VWD [ Sutherland et al , Casari et al ].
Duplications of one or two exons have also been reported [ Boisseau et al , Obser et al , Veyradier et al ]. Gene conversion events with VWFP1 occur from the 3' end of intron 27 into the 5' end of exon 28 [ Goodeve ]. Conversions of 6 bp to bp are most commonly seen and have been reported in VWD types 1, 2B, 2M, and 3.
They have been reported in both multiethnic and Indian populations in higher proportions than often found in other studies [ Gupta et al , Kasatkar et al ]. Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants. See Quick Reference for an explanation of nomenclature.
Examples of the most frequent variants identified in each VWD type are shown. Normal gene product. The 2,amino acid VWF protein comprises:. VWF has two sites of synthesis: endothelial cells and megakaryocytes, the precursors of platelets. During synthesis, tail-to-tail disulfide-linked dimers are formed through the CK domains, followed by head-to-head VWF oligomers of up to 40 dimers in length.
Abnormal gene product. Abnormalities in VWF depend on the type of pathogenic variant. The protein and nucleotide abnormalities both play a role in determining VWD type:. The von Willebrand factor LOVD database currently lists more than unique variants representing more than 1, affected individuals.
Table 5 summarizes the numbers of affected individuals with propeptide and mature VWF pathogenic variants and the ratio between the two. Summary of separate patient entries per VWD type.
Only a single entry for each patient is included; multiple entries are omitted. Professor Goodeve's web page. Professor James's web page. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.
For questions regarding permissions or whether a specified use is allowed, contact: ude. Turn recording back on. National Center for Biotechnology Information , U.
GeneReviews by Title. Search term. GeneReviews Advanced Search Help. Summary Clinical characteristics. Type 2 subtypes include: Type 2A, which usually manifests as mild-to-moderate mucocutaneous bleeding;. Type 2B, which typically manifests as mild-to-moderate mucocutaneous bleeding that can include thrombocytopenia that worsens in certain circumstances;.
Genetic counseling. AD inheritance. Most affected individuals have an affected parent. The proportion of cases caused by de novo pathogenic variants is unknown.
AR inheritance. Carrier testing for family members at risk for AR VWD is possible once the pathogenic variants have been identified in the family. Diagnosis Several guidelines and testing algorithms have been published [ Keeney et al , Nichols et al , Lassila et al , Laffan et al ].
Figure 1. Figure 2. Type 2. Suggestive Findings Von Willebrand disease VWD should be suspected in individuals with excessive mucocutaneous bleeding including the following: Bruising without recognized trauma.
Bleeding from the gums after brushing or flossing teeth or prolonged bleeding following dental cleaning or dental extractions. Clinical Laboratory Testing Screening tests Complete blood count CBC may be normal, but could also show a microcytic anemia if the individual is iron deficient or a low platelet count thrombocytopenia , specifically in type 2B VWD.
Although some laboratories may also include a skin bleeding time and platelet function analysis PFA closure time in their evaluation of an individual with suspected VWD, these tests lack sensitivity in persons with mild bleeding disorders. Ristocetin cofactor activity: all assays that use platelets and ristocetin.
VWF multimer analysis. Normal plasma contains VWF ranging from dimers to multimers comprising more than 40 dimers and molecular weight into gigadaltons. Abnormalities in satellite "triplet" band patterns can give clues as to pathogenesis and help to classify subtypes of type 2 VWD [ Budde et al ].
Ristocetin-induced platelet agglutination RIPA. Ability of VWF to agglutinate platelets at two to three concentrations of ristocetin. Useful, but not widely used to identify type 2N VWD. Ability of VWF to bind to collagen a sub-endothelial matrix component. Used to help define functional VWF discordance i. Currently, this analysis is undertaken as part of the newer activity assays. Table 1. Increased agglutination at low concentrations of ristocetin.
Molecular Genetic Testing Molecular genetic testing approaches can include single- gene testing , use of a multigene panel , and more comprehensive genomic testing : Single- gene testing. A multigene panel that includes VWF and other genes of interest see Differential Diagnosis may be considered. Note: 1 The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. More comprehensive genomic testing when available including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered e. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 2. Clinical Characteristics Clinical Description Von Willebrand disease VWD is a congenital bleeding disorder; however, symptoms may only become apparent on hemostatic challenge and bleeding history may become more apparent with increasing age. Bleeding scores BS have been documented in several cohort studies and give an indication of the range of bleeding severity associated with different VWD types: Table 3.
The higher the bleeding score, the greater the bleeding severity. Individuals with type 2A VWD usually present with mild to moderate mucocutaneous bleeding [ Veyradier et al ]. Individuals typically present with mild-moderate mucocutaneous bleeding. Thrombocytopenia may be present. A hallmark of type 2B VWD is a worsening of thrombocytopenia during stressful situations, such as severe infection or during surgery or pregnancy, or if treated with desmopressin [ Federici et al ].
Individuals typically present with mild-moderate mucocutaneous bleeding symptoms, but bleeding episodes can be severe, particularly in the presence of very low or absent VWF:RCo [ Castaman et al , Larsen et al ].
Symptoms are essentially the same as those seen in mild hemophilia A and include excessive bleeding at the time of surgery or procedures as both disorders result from reduced FVIII:C [ van Meegeren et al ].
Affected individuals present with reduced or absent response to infused VWF concentrates or, in rare cases, with anaphylactic reaction. Individuals who have had multiple transfusions are at highest risk for this complication. Those resulting in higher VWF levels are often incompletely penetrant. Nomenclature Changes in nomenclature: von Willebrand's disease has been replaced by von Willebrand disease. Prevalence VWD affects 0. Alternatively, molecular genetic testing can be used to distinguish the two disorders.
Both molecular and phenotypic testing have some fallibilities in interpretation. The two disorders require different treatment. Lymphoproliferative or plasma cell proliferative disorders, paraproteinemias monoclonal gammopathy of unknown significance [MGUS] , multiple myeloma, and Waldenstrom macroglobulinemia. Antibodies against VWF have been detected in some of these cases.
Autoimmune disorders including systemic lupus erythrematosus SLE , scleroderma, and antiphospholipid antibody syndrome. Markedly increased blood platelet count e. Removal of VWF from circulation by aberrant binding to tumor cells e.
Management Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with von Willebrand disease VWD , the following evaluations are recommended: A personal and family history of bleeding to help predict severity and tailor treatment. Screening for hepatitis B and C as well as HIV if the diagnosis is type 3 VWD or if the individual received blood products or plasma-derived clotting factor concentrates before Baseline serum concentration of ferritin to assess iron stores, as many individuals with VWD particularly women with menorrhagia are iron deficient.
Gynecologic evaluation for women with menorrhagia [ Rodeghiero ]. Treatment of Manifestations See Nichols et al  full text , Castaman et al  full text , and Laffan et al  full text for treatment guidelines. Desmopressin Most individuals with type 1 VWD and some with type 2 VWD respond to intravenous or subcutaneous treatment with desmopressin [ Castaman et al , Federici , Leissinger et al ], which promotes release of stored VWF and raises levels three- to fourfold.
Intranasal preparations are also available. It has been used successfully to cover delivery in women with type 1 VWD and also for a proportion of pregnant women with type 2 VWD where a desmopressin trial has previously proved efficacious [ Castaman et al b ] see Pregnancy Management. In persons who do not tolerate desmopressin or who have a poor VWF response, clotting factor concentrate is required.
In those who are non-responsive to desmopressin i. Plasma-derived concentrates are prepared from pooled blood donations from many donors. Virus inactivation procedures eliminate potential pathogens. Fibrinolytic inhibitors i. Hormonal treatments i. Treatments used most commonly were combined oral contraceptives, tranexamic acid, and desmopressin as first- and second-line therapies, whereas VWF concentrate was the most common third-line therapy used by 13 women 1.
Review of information on 88 women from six published studies showed that a VWF dose of IU kg -1 reduced menorrhagia on days one to six of the menstrual cycle in women. Indirect treatment with fibrinolytic inhibitors or hormones is often effective. Responsiveness to desmopressin is variable and should be confirmed prior to therapeutic use. Indirect treatments can be beneficial.
Desmopressin is not effective in type 3 VWD. Indirect treatments may also be beneficial. Pediatric Issues Special considerations for the care of infants and children with VWD include the following: Infant males should be circumcised only after consultation with a pediatric hemostasis specialist.
VWF levels are higher in the neonatal period [ Klarmann et al ]; thus, phenotypic testing for milder forms of VWD should be delayed until later in childhood.
Prevention of Secondary Complications Desmopressin should be used with caution, particularly in those younger than age two years, because of the potential difficulty in restricting fluids in this age group. Surveillance Individuals with milder forms of VWD can benefit from being followed by treatment centers with experience in the management of bleeding disorders.
Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic at-risk relatives of an affected individual to allow early diagnosis and treatment as needed [ Goodeve ]. Evaluations can include: Molecular genetic testing if the pathogenic variant s in the family are known;.
VWD hemostasis factor assays if the pathogenic variant s in the family are not known. Pregnancy Management VWF levels increase throughout pregnancy with the peak occurring four hours after delivery [ James et al ]. Genetic Counseling Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions.
The proportion of cases caused by a de novo VWF variant is unknown. If the VWF pathogenic variant causing autosomal dominant VWD found in the proband cannot be detected in the leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or de novo pathogenic variant in the proband. Neither possibility has been sufficiently investigated to comment on relative likelihood of occurrence.
The family history of some individuals diagnosed with AD VWD may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the recognition of symptoms, or delayed onset of significant hemostatic challenges in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations e.
The sibs of a proband with clinically unaffected parents are still at increased risk for the disorder because of the possibility of reduced penetrance in a parent. Heterozygotes carriers of type 3 VWD are often asymptomatic. Heterozygotes carriers of type 2N VWD are often asymptomatic. However, a small proportion may show some mild bleeding symptoms and may be diagnosed with type 1 VWD.
Carrier Heterozygote Detection Carrier testing for at-risk relatives requires prior identification of the VWF pathogenic variant s in the family. Related Genetic Counseling Issues See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.
Family planning The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling including discussion of potential risks to offspring and reproductive options to young adults who are affected , are carriers, or are at risk of being carriers. Prenatal Testing and Preimplantation Genetic Diagnosis Once the VWF pathogenic variant s have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for von Willebrand disease are possible.
Medline Plus. Diagnosis, Evaluation and Management of von Willebrand Disease. Von Willebrand disease. Table A. Table B. Figure 3. Incompletely penetrant, dominantly inherited missense variants e. Pathogenic variants are predominantly located in exon 28, affecting the A2 domain and to a lesser extent the A1 domain. Pathogenic variants in the D3 assembly exons 22 and have been reported in dominant disease [ Schneppenheim et al ]. Type 2B pathogenic variants such as p. ProLeu and p.
Small numbers of variants that impair binding to collagen types I and III are located in the A3 domain encoded by exons [ Keeling et al , Veyradier et al ] and in the A1 domain, where they impair binding to collagen types IV and VI [ Flood et al , Flood et al ].
The 2N pathogenic variant p. ArgTrp is also relatively frequent in affected European individuals. Table 4. TyrCys 28 2A c. SerLeu 28 2A c. ArgTrp 28 2B c. ProLeu 28 2B c. ProGlu 28 2B c. ArgLeu 28 2B c. ValMet 28 2B c. ArgGln 28 2B c. ArgCys 28 2M c. ValIle 28 2M c. IlePhe 28 2N c. ThrMet 18 2N c. ArgTrp 19 2N c. ArgGln 20 3 c. ProArgfsTer31 18 3 c. ArgTer 28 3 c. ArgTer Binding collagen in the sub-endothelium at sites of vascular damage, which initiates repair through platelet recruitment and clot formation plus binding; and.
Protecting FVIII from premature proteolytic degradation and transporting it to sites where fibrin generation is required. Type 1. Missense variants predominate but may affect VWF through different mechanisms. Intracellular retention is a common mechanism for type 1 VWD pathogenicity [ Eikenboom et al , Eikenboom et al ]. Haploinsufficiency resulting from a heterozygous null allele results in reduced VWF expression in a small proportion of cases.
Type 2A. Missense variants result in a loss of high- and sometimes intermediate-molecular-weight multimers through a number of mechanisms that may act together: 1 impaired dimer assembly, 2 impaired multimer assembly, 3 enhanced susceptibility to VWF cleaving protease encoded by ADAMTS13 [ Hassenpflug et al ], and 4 intracellular retention [ Schneppenheim et al ].
Type 2B. Higher-molecular-weight multimers bind platelets preferentially, favoring their loss. Type 2M. Type 2N. Type 3. Both alleles are affected by pathogenic variants null or missense that result in lack of VWF secretion from the cell. Some may impair VWF multimerization, resulting in intracellular retention and lack of secretion into plasma. Table 5. Principles of care for the diagnosis and treatment of von Willebrand disease.
Available online. Accessed Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel. Br J Haematol. The diagnosis, evaluation, and management of von Willebrand disease includes a more detailed version and synopsis of the Nichols et al guidelines and patient education information.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. Sadler JE. Chap Phenotypic and molecular characterisation of type 3 von Willebrand disease in a cohort of Indian patients. Thromb Haemost.
The role of prophylaxis in bleeding disorders. Management of pregnancy in type 2B von Willebrand disease: case report and literature review. Platelet-dependent von Willebrand factor activity. J Thromb Haemost. An unexpected transmission of von Willebrand disease type 3: the first case of maternal uniparental disomy The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles.
There may be a family history of specific haematological diagnoses, or there may be more general notes about bleeding tendencies in the maternal history. Bleeding in an otherwise well infant may be a marker of deficiency in a component of the haemostatic system. There are a number of coagulation factor defects that fall under the general heading of haemophilia. Intracranial haemorrhage ICH or significant extracranial bleeding may be the only presenting symptom.
The incidence is approximately male births. Around one-third are sporadic cases diagnosed following bleeding events. Von Willebrand Disease is also classified as a haemophilia although it is clinically less severe than Factor VIII and IX Deficiencies and is not usually diagnosed in the newborn period.
It is most commonly inherited as an autosomal dominant trait with a mild to moderate bleeding tendency.
There is variable clinical and laboratory expression of platelet dysfunction and factor VIII deficiency. There are 3 different recognised types of vWD, depending on qualitative or quantitative abnormalities of vWF. There are very few reports of newborn infants with bleeding secondary to vWD. The most common manifestations in children and adults are nosebleeds and easy bruising.
Diagnosis is made by platelet function analysis PFA and specific tests for vW antigen and activity. Bleeding times are rarely performed.
See the Vitamin K guideline and Vitamin K drug protocol. This diagnosis should be considered in infants who appear to bleed excessively easily, particularly if there is major evidence of haemorrhage e. Deficiency is characterised by increased PT due to reduced active prothrombin. Babies born to mothers on anticonvulsants phenytoin, carbamazepine are at increased risk. VKDB classically presents between days of life in breastfed babies who did not receive prophylactic vitamin K at birth.
It may also occur late, between weeks of age, presenting with ICH and in association with previously undetected hepatic dysfunction. These are conditions which predispose to thrombosis. The classic presentation of Protein C deficiency is purpura fulminans occurring within hours or days of birth. Infants with homozygous Protein C deficiency often have significant in utero thrombotic events cerebral or ophthalmic and severe DIC and large vein thromboses.
Heterozygous Protein C deficiency has been associated with neonatal thrombotic events. Coagulation screens are usually normal but may show an elevated platelet count and increased fibrin degradation products.
Protein S deficiency has been very rarely reported in neonates. Antithrombin deficiency most commonly presents in adulthood, although there are reports of neonates with significant thromboses. This may be found because of investigations performed on mothers with a history or pre-eclampsia or recurrent miscarraige.
It is generally associated with an increased lifetime risk of thrombosis, although most individuals with Factor V Leiden mutation will remain well. A severe neonatal form has been described. These are hereditary conditions with decreased or absent synthesis of at least one globin chain. The red cell changes are mild and may not be detected clinically or may present with mild microcytic anaemia that should be differentiated from iron deficiency.
Usually this presents as a transfusion dependent chronic anaemia, but the severity of disease is dependent on the interaction of a number of complex genetic factors, and some patients are not transfusion dependent even though they have a moderate anaemia. This is relatively common in neonates. It may be due to a variety of causes including infection, AV malformations, alloimmune haemolysis such as ABO incompatibility , exposure to toxins including bacterial toxins and oxidant drugs, haemoglobinopathies, red cell enzyme and membrane abnormalities.
Often, no specific underlying cause is found, as in the transient Infantile Pyknocytosis often seen weeks after birth. Vitamin E deficiency should be rare nowadays but also needs to be considered in some cases, particularly very premature infants. It is important to look at the blood film for evidence of haemolysis spherocytes, cell fragment, polychromatic cells or infection.
There may be prolonged or exaggerated jaundice. If no apparent cause is found, then further testing such as investigations for red cell membrane defects or unusual haemoglobinopathies should be discussed with the on-call paediatric haematologist. This is a relatively common abnormality of red cell metabolic enzymes, inherited as a sex-linked disorder in males although females can be affected due to lyonisation.
G6PD is required to protect the haemoglobin and the red cell membrane from oxidative damage. The clinical presentation of G6PD deficiency varies. The severe forms can lead to severe haemolysis, which can be spontaneous or after exposure to drugs or chemicals including fava bean and camphor or naphthalene used as insect repellents in closets. Infection can also precipitate haemolysis. It commonly manifests as severe jaundice in affected male babies.
Infants from these ethnic groups who develop jaundice severe enough to require phototherapy should be investigated. Haematological Disorders in Neonates. September Haemophilia and Comments. Factor V Leiden Mutation. Intravascular Haemolysis. GlucosePhosphate Dehydrogenase Deficiency. Vitamin K Deficiency Bleeding. The normal neonatal ranges for factor IX are decreased compared with adults, so diagnosis of a mild deficiency can be difficult. Avoid intramuscular injections. Vaccinations may be given subcutaneously.
Vitamin K should be given orally until the results of the factor assays are available. Closely monitor for signs of ICH. Arrange a screening Head Ultrasound prior to discharge. Discuss with a paediatric haematologist.
Prophylactic factor replacement should not be given due to the risk of inhibitor development. No investigations are necessary unless unexplained significant bleeding discuss with haematology. Levels of vWF are physiologically increased in the neonatal period. Prophylactic vitamin K at birth Referral to paediatric haematology. Intramuscular Vitamin K prophylaxis at birth intramuscular is preferred over oral preparation for efficiency and reliability of administration.
Consider prophylaxis in infants with known liver disease. Discuss with a paediatric haematologist Infants presenting with neonatal stroke may need investigation which is usually repeated around 3- 6 months. Avoid indwelling central intravenous or intra-arterial catheters Fresh frozen plasma or replacement products Protein C or Antithrombin concentrates if symptomatically indicated after discussion with a paediatric haematologist.
No investigations are indicated at birth or in the neonatal period. No specific investigations. FBC may be normal in thalassaemia traits. Haematology follow-up as indicated by particular haemoglobinopathy. Exclude infection Group and Direct Antiglobulin test Reticulocyte count GlucosePhosphate Dehydrogenase screen Pyruvate Kinase screen Haemoglobinopathy study Vitamin E level Blood from both parents for Haemoglobin and blood film to evaluate red cell morphology.
Red Cell Transfusions may be required to maintain a normal haemoglobin Monitor and treat neonatal jaundice Discuss with a paediatric haematologist. If clinically appropriate, consider repeating the G6PD study when the acute haemolysis has settled. Blood film may show evidence of haemolysis with red cell fragments, spherocytes, and "bite" cells. If G6PD confirmed, advise parents regarding medications, foods and other factors which may precipitate acute haemolysis.
Advise parents of early recognition of symptoms and signs of acute haemolysis, which can be a haematological emergency. Kulkarni, R.
Intracranial and extracranial hemorrhages in newborns with haemophilia: a review of the literature. J Pediatr Hematol Oncol. Ljung R. Intracranial haemorrhage in haemophilia A and B.
Brit J Haematol ; Richards, M. Combescure C. Neonatal bleeding in haemophilia: a European cohort study. Br J Haematol ; Perinatal management of newborns with haemophilia. British J Haematology. Kenet, G. Bleeding disorders in neonates. Haemophilia S5 Chalmers, E.
Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A. Haemophilia ; Smith, A. Intracranial haemorrhage in newborns with haemophilia: the role of screening radiologic studies in the first 7 days of life.