Re: Addressing Heavy Menstrual Periods Naturally at Ask Tony Isaacs: Featuring Luella May

Another cause of heavy menstrual bleeding is the bleeding disorder von wilebrands. A very common bleeding disorder affecting 1 in 100 people. Mild versions often go undiagnosed and only discovered due to chronic nose bleeds or heavy menstrual bleeding. This disease, unlike hemophilia, can be passed on by the father as well as the mother. My daughter inherited VW2b from her dad. He has the nosebleeds and she has heavy periods. The only time VW is a concern for either of them is if they have surgery or should suffer severe trauma and injury. We've learned in the past year that an infusion of factor 8 (humuate) before surgery and after surgery is all that's needed to prevent excess bleeding. We haven't tried yarrow for my daughter's periods yet. Since she can't take motrin and tylenol doesn't help cramps, she takes lobelia (4) and cramp bark (4) with tylenol (2) for the pain. It does help some, doesn't get rid of the cramps completely though. She absolutely hates taking pills and will only take them if the pain is really bad. I haven't been able to convince her to try the yarrow yet. Right now, we're trying iodoral (iodine) to see if that helps. Since she hates pills and I forget to set them out every day, she's been not taking them more often than not. But there was a month or two last year when she had a less painful and somewhat lighter flow when I'd been a little more vigilant and made sure she took it every day.

Von Willebrand disease

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von Willebrand disease
Classification and external resources
ICD-10	D 68.0
ICD-9	286.4
OMIM	193400
DiseasesDB	14007
eMedicine	ped/2419
MeSH	D014842
GeneReviews	von Willebrand Disease

von Willebrand disease (vWD) is the most common hereditary coagulation abnormality described in humans, although it can also be acquired as a result of other medical conditions. It arises from a qualitative or quantitative deficiency of von Willebrand factor (vWF), a multimeric protein that is required for platelet adhesion. It is known to affect humans and dogs (notably Doberman Pinschers), and rarely in swine, cattle, horses, and cats. There are four types of hereditary vWD. Other factors including ABO blood groups may also play a part in the severity of the condition.

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[edit]Signs and symptoms

The various types of vWD present with varying degrees of bleeding tendency, usually in the form of easy bruising, nosebleeds and bleeding gums. Women may experience heavy menstrual periods and blood loss during childbirth.

Severe internal or joint bleeding is rare (which only occurs in type 3 vWD).

[edit]Diagnosis

When suspected, blood plasma of a patient needs to be investigated for quantitative and qualitative deficiencies of vWF. This is achieved by measuring the amount of vWF in a vWF antigen assay and the functionality of vWF with a glycoprotein (GP)Ib binding assay, acollagen binding assay or, a ristocetin cofactor activity (RiCof) or ristocetin induced platelet agglutination (RIPA) assays. Factor VIII levels are also performed because factor VIII is bound to vWF which protects the factor VIII from rapid breakdown within the blood. Deficiency of vWF can therefore lead to a reduction in factor VIII levels. Normal levels do not exclude all forms of vWD: particularly type 2 which may only be revealed by investigating platelet interaction with subendothelium under flow (PAF), a highly specialized coagulation study not routinely performed in most medical laboratories. A platelet aggregation assay will show an abnormal response to ristocetin with normal responses to the other agonists used. A platelet function assay (PFA) will give an abnormal collagen/adrenaline closure time and in most cases (but not all) a normal collagen/ADP time. Type 2N can only be diagnosed by performing a "factor VIII binding" assay. Detection of vWD is complicated by vWF being an acute phase reactant with levels rising in infection, pregnancy and stress.

Other tests performed in any patient with bleeding problems are a complete blood count (especially platelet counts), APTT (activated partial thromboplastin time), prothrombin time, thrombin time and fibrinogen level. Testing for factor IX may also be performed if hemophilia Bis suspected. Other coagulation factor assays may be performed depending on the results of a coagulation screen. Patients with von Willebrand disease will typically display a normal prothrombin time and a variable prolongation of partial thromboplastin time.

Condition	Prothrombin time	Partial thromboplastin time	Bleeding time	Platelet count
Vitamin K deficiency or Warfarin	prolonged	prolonged	unaffected	unaffected
Disseminated intravascular coagulation	prolonged	prolonged	prolonged	decreased
Von Willebrand disease	unaffected	prolonged	prolonged	unaffected
Haemophilia	unaffected	prolonged	unaffected	unaffected
Aspirin	unaffected	unaffected	prolonged	unaffected
Thrombocytopenia	unaffected	unaffected	prolonged	decreased
Early Liver failure	prolonged	unaffected	unaffected	unaffected
End-stage Liver failure	prolonged	prolonged	prolonged	decreased
Uremia	unaffected	unaffected	prolonged	unaffected
Congenital afibrinogenemia	prolonged	prolonged	prolonged	unaffected
Factor V deficiency	prolonged	prolonged	unaffected	unaffected
Factor X deficiency as seen in amyloid purpura	prolonged	prolonged	unaffected	unaffected
Glanzmann's thrombasthenia	unaffected	unaffected	prolonged	unaffected
Bernard-Soulier syndrome	unaffected	unaffected	prolonged	decreased

[edit]Classification and types

[edit]Classification

There are four hereditary types of vWD described - type 1, type 2, type 3, and platelet-type. There are inherited and acquired forms of vWD. Most cases are hereditary, but acquired forms of vWD have been described. The International Society on Thrombosis and Haemostasis's (ISTH) classification depends on the definition of qualitative and quantitative defects.^[1]

[edit]Type 1

Type 1 vWD (60-80% of all vWD cases) is a quantitative defect (heterozygous for the defective gene) but may not have clearly impaired clotting, most patients usually end up leading a nearly normal life. Trouble may arise in the form of bleeding following surgery (including dental procedures), noticeable easy bruising, or menorrhagia (heavy periods). Decreased levels of vWF are detected (10-45% of normal, i.e. 10-45 IU).

[edit]Type 2

Type 2 vWD (20-30%) is a qualitative defect and the bleeding tendency can vary between individuals. There are normal levels of vWF, but the multimers are structurally abnormal, or subgroups of large or small multimers are absent. Four subtypes exist: 2A, 2B, 2M and 2N.

[edit]Type 2A

This is an abnormality of the synthesis or proteolysis of the vWF multimers resulting in the presence of small multimer units in circulation. Factor VIII binding is normal. It has a disproportionately low ristocetin co-factor activity compared to the von Willebrand's antigen.

[edit]Type 2B

This is a "gain of function" defect leading to spontaneous binding to platelets and subsequent rapid clearance of the platelets and the large vWF multimers. A mild thrombocytopenia may occur. The large vWF multimers are absent in the circulation and the factor VIII binding is normal. Like type 2A, the RiCof:vWF antigen assay is low when the patient's platelet-poor plasma is assayed against formalin-fixed, normal donor platelets. However, when the assay is performed with the patient's own platelets ("platelet-rich plasma"), a lower-than-normal amount of ristocetin causes aggregation to occur. This is due to the large vWF multimers remaining bound to the patient's platelets. Patients with this sub-type are unable to use desmopressin as a treatment for bleeding, because it can lead to unwanted platelet aggregation.

[edit]Type 2M

Patients with type 2M von Willebrand disease have similar lab results to those who have type 2A von Willebrand disease. It is characterized by a platelet function deficiency and can be acquired by a gene mutation. This is caused by a decrease of high–molecular weight multimers. Decreased von Willebrand activity was observed in lab findings. However, the von Willebrand factor antigen, factor VIII, was found to be within the reference range.

[edit]Type 2N (Normandy)

This is a deficiency of the binding of vWF to factor VIII. This type gives a normal vWF antigen level and normal functional test results but has a low factor VIII. This has probably led to some 2N patients being misdiagnosed in the past as having hemophilia A, and should be suspected if the patient has the clinical findings of hemophilia A but a pedigree suggesting autosomal, rather than X-linked, inheritance.

[edit]Type 3

Type 3 is the most severe form of vWD (homozygous for the defective gene) and may have severe mucosal bleeding, no detectable vWF antigen, and may have sufficiently low factor VIII that they have occasional hemarthroses (joint bleeding), as in cases of mild hemophilia.

Platelet-type (also known as pseudo-vWD or platelet-type [pseudo] vWD) Platelet-type vWD is an autosomal dominant type of vWD caused by gain of function mutations of the vWF receptor on platelets; specifically, the alpha chain of the glycoprotein Ib receptor (GPIb). This protein is part of the larger complex (GPIb/V/IX) which forms the full vWF receptor on platelets. The ristocetin activity and loss of large vWF multimers is similar to type 2B, but genetic testing of vWF will reveal no mutations.

[edit]Acquired von Willebrand disease

Acquired vWD can occur in patients with autoantibodies. In this case the function of vWF is not inhibited but the vWF-antibody complex is rapidly cleared from the circulation.

A form of vWD occurs in patients with aortic valve stenosis, leading to gastrointestinal bleeding (Heyde's syndrome). This form of acquired vWD may be more prevalent than is presently thought.

Acquired vWD has also been described in the following disorders: Wilms' tumour, hypothyroidism and mesenchymal dysplasias.

[edit]Pathophysiology

For the normal function of the coagulation factor, see von Willebrand factor.

vWF is mainly active in conditions of high blood flow and shear stress. Deficiency of vWF therefore shows primarily in organs with extensive small vessels, such as the skin, the gastrointestinal tract and the uterus. In angiodysplasia, a form of telangiectasia of the colon, shear stress is much higher than in average capillaries, and the risk of bleeding is increased concomitantly.

In more severe cases of type 1 vWD, genetic changes are common within the vWF gene and are highly penetrant. In milder cases of type 1 vWD there may be a complex spectrum of molecular pathology in addition to polymorphisms of the vWF gene alone.^[2] The individual's ABO blood group can influence presentation and pathology of vWD. Those individuals with blood group O have a lower mean level than individuals with other blood groups. Unless ABO group–specific vWF:antigen reference ranges are used, normal group O individuals can be diagnosed as type I vWD, and some individuals of blood group AB with a genetic defect of vWF may have the diagnosis overlooked because vWF levels are elevated due to blood group.^[3]

[edit]Genetics

von Willebrand disease types I and II are inherited in an autosomal dominant pattern.

von Willebrand disease type III (and sometimes II) is inherited in an autosomal recessive pattern.

The vWF gene is located on chromosome twelve (12p13.2). It has 52 exons spanning 178kbp. Types 1 and 2 are inherited as autosomal dominant traits and type 3 is inherited as autosomal recessive. Occasionally type 2 also inherits recessively.

[edit]Epidemiology

The prevalence of vWD is about 1 in 100 individuals.^[4] However the majority of these people do not have symptoms. The prevalence of clinically significant cases is 1 per 10,000.^[4] Because most forms are rather mild, they are detected more often in women, whose bleeding tendency shows during menstruation. It may be more severe or apparent in people with blood type O.

[edit]Therapy

Patients with vWD normally require no regular treatment, although they are always at increased risk for bleeding. For women with heavy menstrual bleeding, the combined oral contraceptive pill may be effective in reducing bleeding or in reducing the length or frequency of periods. Prophylactic treatment is sometimes given for patients with vWD who are scheduled for surgery. They can be treated with human derived medium purity factor VIII concentrates complexed to vWF (antihemophilic factor, more commonly known as Humate-P) Mild cases of vWD can be trialled on desmopressin (1-desamino-8-D-arginine vasopressin, DDAVP) (desmopressin acetate, Stimate), which works by raising the patient's own plasma levels of vWF by inducing release of vWF stored in the Weibel-Palade bodies in the endothelial cells.

[edit]History

vWD is named after Erik Adolf von Willebrand, a Finnish pediatrician (1870–1949).^[5] He first described the disease in 1926.

[edit]Sources

Harrison's textbook of Internal Medicine, Chapter 177.
Sadler JE (1998). "Biochemistry and genetics of von Willebrand factor". Annu. Rev. Biochem. 67: 395–424. doi:10.1146/annurev.biochem.67.1.395. PMID 9759493.
Mannucci PM; Mannucci, Pier Mannuccio (2004). "Treatment of von Willebrand's Disease". N. Engl. J. Med. 351 (7): 683–94. doi:10.1056/NEJMra040403. PMID 15306670.
Laffan M, Brown SA, Collins PW, et al. (2004). "The diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organization". Haemophilia 10 (3): 199–217. doi:10.1111/j.1365-2516.2004.00894.x. PMID 15086318.
Williams Hematology, 7th edition, Grune and Stratton, chapters112 (p. 1806) and118 (p. 1937)*

[edit]See also

Bernard-Soulier syndrome, caused by a deficiency in the vWF receptor, GPIb
Blood diseases
Purpura secondary to clotting disorders

[edit]References

^ Sadler JE (1994). "A revised classification of von Willebrand disease. For the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis".Thromb. Haemost. 71 (4): 520–5. PMID 8052974.
^ James P, Notley C, Hegadorn C, Leggo J, Tuttle A, Tinlin S, Brown C, Andrews C, Labelle A, Chirinian Y, O'Brien L, Othman M, Rivard G, Rapson D, Hough C, Lillicrap D (2007). "The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study". Blood 109 (1): 145–54. doi:10.1182/blood-2006-05-021105. PMID 17190853.
^ Gill, JC; Endres-Brooks J, Bauer PJ, Marks WJ, Montgomery RR (1987). "The effect of ABO blood group on the diagnosis of von Willebrand disease". Blood 69 (6): 1691–5. PMID 3495304.
^ ^a ^b "Molecular basis of von Willebrand disease and its clinical implications". Haematologica 89 (9): 1036. 1 September 2004. PMID 15377463.
^ doctor/2690 at Who Named It?

[edit]External links

GeneReviews/NCBI/NIH/UW entry on von Willebrand Disease
Sheffield.ac.uk, International repository on vWF mutations (University of Sheffield)
Hemophilia.org
Haemophilia.org.uk
WFH.org, World Federation of Hemophilia
Ukhcdo.org UK Haemophilia Centre Directors Organisation
NIH.gov, Clinical Practice Guidelines by the U.S. National Heart, Lung, and Blood Institute