Platelets
Platelets or thrombocytes are the cell fragments circulating in the blood that are involved in the cellular mechanisms of primary hemostasis leading to the formation of blood clots.1 Dysfunction or low levels of platelets predisposes to bleeding, while high levels, although usually asymptomatic, may increase the risk of thrombosis.
Platelets are anuclear and disc shaped; they measure 1.5–3.0 μm in diameter. Human body has a very limited reserve of platelets, so they can be rapidly depleted. Platelets contain RNA, mitochondria, a canalicular system, and several different types of granules; lysosomes containing acid hydrolases, dense bodies containing ADP, ATP serotonin and calcium and alpha granules containing fibrinogen, factor V, vitronectin, thrombospondin and von Willebrand factor. The contents are released upon activation of the platelets.
Platelets are produced in the bone marrow & the progenitor cell for platelets is the megakaryocyte. Megakaryocyte is about twelve times larger than an erythrocyte, possesses a lobed nucleus and sheds platelets into the circulation.1 Thrombopoietin is a hormone, mainly produced by the liver, that stimulates platelet production. It is bound to circulating platelets; if platelet levels are adequate, serum levels remain low. If the platelet count is decreased, more thrombopoeitin circulates freely and increases platelet production.
The circulating life of a platelet is 8–10 days.1 After this it is sequestered in the spleen. Decreased function (or absence) of the spleen may increase platelet counts, while hypersplenism (overactivity of the spleen, e.g. in Gaucher’s disease, leukemia, and cirrhosis) may lead to increased elimination and hence low platelet counts.
Platelets are activated when brought into contact with collagen (which is exposed when the endothelial blood vessel lining is damaged), thrombin, ADP, receptors expressed on white blood cells or the endothelial cells of the blood vessels, a negatively charged surface (e.g., glass), or several other activating factors. Once activated, they release a number of different coagulation factors and platelet activating factors. Platelet activation further results in the scramblase-mediated transport of negatively charged phospholipids to the platelet surface. These phospholipids provide a catalytic surface (with the charge provided by phosphatidylserine and phosphatidylethanolamine) for the tenase and prothrombinase complexes. The platelets adhere to each other via adhesion receptors or integrins, and to the endothelial cells in the wall of the blood vessel forming a haemostatic plug in conjunction with fibrin. The high concentration of myosin and actin filaments in platelets are stimulated to contract during aggregation, further reinforcing the plug. The most abundant platelet adhesion receptor is glycoprotein (GP) IIb/IIIa; this is a calcium-dependent receptor for fibrinogen, fibronectin, vitronectin, thrombospondin and von Willebrand factor (vWF). Other receptors include GPIb-V-IX complex (vWF) and GPVI (collagen)

A scanning electron microscope (SEM) image of normal circulating human blood.
Red blood cells, several white blood cells including lymphocytes, a monocyte, a neutrophil, and many small disc-shaped platelets can be seen.
Platelet Activators.
• Collagen2
Collagen is exposed when endothelial blood vessel lining is damaged, and binds to its receptors GPVI and α2b-β1 on the platelet surface.
• Von Willebrand factor 2
Circulates in the blood and binds to its receptor GPIb-IX-V on the platelet surface.
• Thrombin
Primarily through cleavage of the extracellular domain of PAR1 and PAR4;
• Thromboxane A2 (TxA2)
Binds to its receptor, TP.
• ADP 2
By the action on its two cell surface receptors, P2Y1 and P2Y12.
• Adrenaline
Activates its receptor (α 2) on the platelet surface. Adrenaline will also activate an inhibitory β 2 receptor on platelets, but this effect is normally masked by its predominant effect on α 2.
• Serotonin
Activates its receptor (5HT-2c) on the platelet surface.
• Human neutrophil elastase (HNE)
Cleaves the αIIbβ3 integrin on the platelet surface;
• P-selectin
Binds to PSGL-1 on endothelial cells and white blood cells and which is normally exposed on the surface of platelets following initial activation by other activators.

Platelet Inhibitors.
• Prostacyclin
Opposes the actions of most platelet agonists by increasing intracellular cAMP levels
• Adenosine
By the action on its cell surface receptor (A2 receptor) by increasing intracellular cAMP levels.
• Nitric oxide
Released by the endothelium and platelets themselves in some instances.
• Clotting factors II, IX, X, XI, XII
• Nucleotidases such as CD39 ecto-ADP’ase break down ADP
• Some drugs
o Aspirin irreversibly inhibits cyclooxygenase-1, preventing positive feedback3
o Clopidogrel inhibits ADP receptors
o Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis
o Abciximab blocks fibrinogen receptors
o β-lactam antibiotics alteration of agonist receptors
o Quinidine calcium channel blocker

Diseases & conditions associated with abnormal platelet counts.
A normal platelet count in a healthy person is between 150,000 and 400,000 per mm³ of blood (150–400 x 109/L).4 95% of healthy people have platelet counts in this range. Some will have statistically abnormal platelet counts while having no abnormality, although the likelihood increases if the platelet count is either very low or very high.
Both thrombocytopenia (thrombopenia) and thrombocytosis may present with coagulation problems. Generally, low platelet counts increase bleeding risks, although there are exceptions, (e.g. immune heparin-induced thrombocytopenia) and thrombocytosis (high platelet counts). Thrombocytosis may lead to thrombosis when the elevated count is due to myeloproliferative disorder.
Low platelet counts are generally not corrected by transfusion unless the patient is bleeding or the count has fallen below 5 x 109/L; it is contraindicated in thrombotic thrombocopenic purpura (TTP) as it fuels the coagulopathy. In patients having surgery, a level below 50 x 109/L is associated with abnormal surgical bleeding, and regional anaesthetic procedures such as epidurals are avoided for levels below 80-100.
Normal platelet counts are not a guarantee of adequate function. In some states the platelets, while being adequate in number, are dysfunctional. For instance, aspirin irreversibly disrupts platelet function by inhibiting cyclooxygenase-1 (COX1), and hence normal hemostasis; normal platelet function may not return until the aspirin has ceased and all the affected platelets have been replaced by new ones, which can take over a week. Similarly uremia; a consequence of renal failure leads to platelet dysfunction that may be ameliorated by the administration of desmopressin.

Diseases & conditions associated with reduced platelet activity.
 Disorders leading to a reduced platelet count:
• Thrombocytopenia
o Idiopathic thrombocytopenic purpura (immune thrombocytopenic purpura (ITP))5
o Thrombotic thrombocytopenic purpura6
o Drug-induced thrombocytopenia7,2, e.g. heparin-induced thrombocytopenia (HIT)
• Gaucher’s disease
• Aplastic anemia
 Alloimmune disorders:
• Fetomaternal alloimmune thrombocytopenia
• Some transfusion reactions.
 Disorders leading to platelet dysfunction or reduced count:
• HELLP syndrome
• Hemolytic-uremic syndrome
• Chemotherapy
• Dengue
 Disorders of platelet adhesion or aggregation:
• Bernard-Soulier syndrome
• Glanzmann’s thrombasthenia
• Scott’s syndrome
• von Willebrand disease
• Hermansky-Pudlak Syndrome
 Disorders of platelet metabolism:
• Decreased cyclooxygenase activity, induced or congenital
• Storage pool defects, acquired or congenital
 Disorders that compromise platelet function:
• Haemophilia
 Disorders featuring an elevated count:
• Thrombocytosis, including benign essential thrombocytosis (elevated counts, either reactive or as an expression of myeloproliferative disease); may feature dysfunctional platelets

Thrombocytopenia.
The presence of a lower blood platelet count than the normal is called thrombocytopenia. This can be due to various causes; due to decreased production, increased destruction, or may be induced by medication.
 Decreased production in:
• vitamin B12 or folic acid deficiency
• leukemia or myelodysplastic syndrome
• Decreased production of thrombopoietin by the liver in liver failure.
• Sepsis, systemic viral or bacterial infection
• Dengue fever can cause thrombocytopenia by direct infection of bone marrow megakaryocytes as well as immunological shortened platelet survival
• Hereditary syndromes
o Thrombocytopenia absent radius syndrome
o Fanconi anemia
o Bernard-Soulier syndrome, associated with large platelets
o May-Hegglin anomaly, the combination of thrombocytopenia, pale-blue leuckocyte inclusions, and giant platelets
o Grey platelet syndrome
o Alport syndrome
 Increased destruction in:
• idiopathic thrombocytopenic purpura (ITP)
• thrombotic thrombocytopenic purpura (TTP)
• hemolytic-uremic syndrome (HUS)
• disseminated intravascular coagulation (DIC)
• paroxysmal nocturnal hemoglobinuria (PNH)
• antiphospholipid syndrome
• systemic lupus erythematosus (SLE)
• post transfusion purpura
• neonatal alloimmune thrombocytopenia (NAITP)
• Splenic sequestration of platelets due to hypersplenism
• Dengue fever has been shown to cause shortened platelet survival and immunological platelet destruction
 Induction by medication in:
• Direct myelosuppression due to:
o Valproic acid
o Methotrexate
o Carboplatin
o Interferon
o Other chemotherapy drugs
• Immunological platelet destruction due to:
o quinidine
o Heparin
Often, low platelet levels do not lead to clinical problems; rather, they are picked up on a routine full blood count. Occasionally, there may be bruising, particularly purpura in the forearms, nosebleeds and/or bleeding gums.
It is vital that a full medical history is elicited, to ensure the low platelet count is not due to a secondary process. It is also important to ensure that the other blood cell types red blood cells, and white blood cells, are not also suppressed.
For the diagnosis of the disease, following laboratory tests are carried out;
 full blood count
 liver enzymes
 renal function
 vitamin B12 level
 folic acid level
 erythrocyte sedimentation rate
 peripheral blood smear.
If the cause for the low platelet count remains unclear, bone marrow biopsy is often undertaken, to differentiate whether the low platelet count is due to decreased production or peripheral destruction.
The main concept in treating thrombocytopenia is to eliminate the underlying problem; discontinuing suspected drugs that cause thrombocytopenia, or treating underlying sepsis.

Gaucher’s Disease.
Gaucher’s disease is the most common of the lipid storage diseases. It is named after the French doctor who originally described it in 1882. It is caused by a deficiency of the enzyme glucocerebrosidase, leading to an accumulation of its substrate, the fatty substance glucocerebroside.
The disease is caused by a defect in the housekeeping gene lysosomal gluco-cerebrosidase (β-glucosidase) on the first chromosome (1q21).2,8 The enzyme catalyses the breakdown of glucocerebroside, a cell membrane constituent of red and white blood cells. The macrophages that clear these cells are unable to eliminate the waste product, which accumulates in fibrils, and turn into Gaucher cells.
Different mutations in the β-glucosidase determine the remaining activity of the enzyme, and, to a large extent, the phenotype.
In the brain, glucocerebroside accumulates due to the turnover of complex lipids during brain development and the formation of the myelin sheath of nerves.
Fatty material can collect in the spleen, liver, kidneys, lungs, brain and bone marrow. Symptoms include enlarged spleen and liver, liver malfunction, skeletal disorders and bone lesions that may cause pain, severe neurologic complications, swelling of lymph nodes and occasionally adjacent joints, distended abdomen, a brownish tint to the skin, anemia, low blood platelets and yellow fatty deposits on the sclera. Persons affected most seriously may also be more susceptible to infection. The disease affects males and females equally. It is the most common lysosomal storage disease.
Gaucher disease has three common clinical subtypes;
Type I ( nonneuropathic type) is the most common form of the disease (more than 99% of cases). It occurs most often among persons of Ashkenazi Jewish heritage. Symptoms may begin early in life or in adulthood and include enlarged liver and grossly enlarged spleen, which can rupture and cause additional complications. Skeletal weakness and bone disease may be extensive. Spleen enlargement and bone marrow replacement cause anemia and leukopenia. The brain is not affected, but there may be lung and, rarely, kidney impairment. Patients in this group usually bruise easily and experience fatigue due to low blood platelets. Depending on disease onset and severity, type 1 patients may live well into adulthood. Many patients have a mild form of the disease or may not show any symptoms.
Type II ( acute infantile neuropathic Gaucher disease) typically begins within 6 months of birth. Symptoms include an enlarged liver and spleen, extensive and progressive brain damage, eye movement disorders, spasticity, seizures, limb rigidity, and a poor ability to suck and swallow. Affected children usually die by age 2.
Type III (the chronic neuronopathic form) can begin at any time in childhood or even in adulthood. It is characterized by slowly progressive but milder neurologic symptoms compared to the acute or type 2 version. Major symptoms include an enlarged spleen and/or liver, seizures, poor coordination, skeletal irregularities, eye movement disorders, blood disorders including anemia and respiratory problems. Patients often live into their early teen years and adulthood.
All three types of Gaucher’s disease are inherited in an autosomal recessive fashion. Both parents must be carriers in order for a child to be affected. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of mutations.
Biochemical abnormalities such as the high alkaline phosphatase, angiotensin-converting enzyme (ACE) and immunoglobulin levels.
The diagnosis is made with genetic testing of the β-glucosidase gene. As there are numerous different mutations, sequencing of the gene is sometimes necessary to confirm the diagnosis. Prenatal diagnosis is available, and is useful when there is a known genetic risk factor.9
For type 1 and most type 3 patients, enzyme replacement treatment with mannose-terminated recombinant glucocerebrosidase, 60 Units/kg, given intravenously every two weeks can dramatically decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations.9 This treatment is becoming the standard in treating Gaucher’s. Successful bone marrow transplantation cures the non-neurological manifestations of the disease, because it introduces a monocyte population with active β-glucosidase. However, this procedure carries significant risk and is rarely performed in Gaucher patients. Surgery to remove the spleen (splenectomy) may be required on rare occasions if the patient is anemic or when the enlarged organ affects the patient’s comfort.9 Blood transfusion may benefit some anemic patients. Other patients may require joint replacement surgery to improve mobility and quality of life. Other treatment options include antibiotics for infections, antiepileptics for seizures and liver transplants. Substrate reduction therapy may prove to be effective in stopping Type 2, as it can cross through the blood barrier into the brain. There is currently no effective treatment for the severe brain damage that may occur in patients with types 2 and 3 Gaucher disease.

Aplastic anaemia.
In this condition bone marrow does not produce sufficient new cells to replenish blood cells.Here, the bone marrow suffers from an aplasia & is unable to function properly. Anemia is the condition of having fewer red blood cells than normal, or fewer than needed to function properly. Typically, anemia refers to low red blood cell counts, but aplastic anemia patients have lower counts of all three blood cell types; red blood cells, white blood cells, and platelets.
One known cause for aplastic anaemia is an autoimmune disorder, where the white blood cells attack the bone marrow.
Aplastic anemia is also associated with exposure to substances such as benzene, radiation, and rarely due to the use of certain drugs, including chloramphenicol, carbamazepine, phenytoin, quinine, and phenylbutazone. Also it is present in up to 2% of patients with acute viral hepatitis
Signs & symptoms of the disease are;
• Anemia with malaise, pallor and associated symptoms
• Thrombocytopenia leading to increased risk of hemorrhage and bruising
• Leukopenia (low white blood cell count), leading to increased risk of infection
The diagnosis can only be made on bone marrow examination. Before this procedure is undertaken, a patient will generally have had other blood tests to find diagnostic clues, including a full blood count, renal function and electrolytes, liver enzymes, thyroid function tests, vitamin B12 and folic acid levels.
Treating aplastic anemia involves suppression of the immune system, an effect achieved by daily medicine intake, or, in more severe cases, a bone marrow transplant, a potential cure but a risky procedure. The transplanted bone marrow replaces the failing bone marrow cells with new ones from a matching donor. The pluripotent stem cells in the bone marrow reconstitute all three blood cell lines, giving the patient a new immune system, red blood cells, and platelets. However, besides the risk of graft failure, there is also a risk that the newly created white blood cells may attack the rest of the body.
Medical therapy of aplastic anemia often includes a short course of anti-thymocyte globulin (ATG or anti-lymphocyte globulin) and several months of treatment with cyclosporin to modulate the immune system. Mild chemotherapy with agents such as cyclophosphamide and vincristine may also be effective. Antibodies therapy, such as ATG, targets T-cells, which are believed to attack the bone marrow. Steroids are generally ineffective.

Foetomaternal alloimmune thrombocytopenia.
In fetomaternal alloimmune thrombocytopenia (Neonatal Alloimmune Thrombocytopenia or NAIT) maternal IgG antibodies (specific for platelet antigens) pass through the placenta and attack platelets in the fetal circulation. This results in the fetus having low numbers of platelets and a tendency for the fetus or neonate to bruise and bleed. Medical treatment is problematic.

HELLP Syndrome.
Hemolytic anemia, Elevated Liver enzymes and Low Platelet count are the main findings of HELLP syndrome, which are also been abbreviated in its name. It is a life-threatening obstetric complication which occurs during the latter stages of pregnancy, or sometimes after childbirth. Its incidence is reported as 0.2-0.6% of all pregnancies. Mortality is 7-35% and perinatal mortality of the child may be up to 40%.10 HELLP usually begins during the third trimester, and usually in Caucasian women over the age of 25. Rarely, cases have been reported as early as 23 weeks gestation. It was identified as a distinct clinical entity by Dr Louis Weinstein in 1982.
The exact cause of HELLP is unknown, but general activation of the coagulation cascade is considered the main underlying problem. Fibrin forms crosslinked networks in the small blood vessels. This leads to a microangiopathic hemolytic anemia: the mesh causes destruction of red blood cells. Additionally, platelets are consumed. As the liver appears to be the main site of this process, downstream liver cells suffer ischemia, leading to periportal necrosis. Other organs can be similarly affected. HELLP syndrome leads to a variant form of disseminated intravascular coagulation (DIC), leading to paradoxical bleeding, which can make emergency surgery a serious challenge.
Often, a patient who develops HELLP syndrome has already been followed up for gestational hypertension, or is suspected to develop high blood pressure and proteinuria. Up to 8% of all cases present after delivery.
There is gradual but marked onset of headaches (30%), blurred vision, malaise (90%), nausea/vomiting (30%), “band pain” around the upper abdomen (65%) and tingling in the extremities. Oedema may occur. Arterial hypertension is a diagnostic requirement, but may be mild. Rupture of the liver capsule and a resultant hematoma may occur. If the patient gets a seizure or coma, the condition has progressed into full-blown eclampsia.11
Patients who present symptoms of HELLP can be misdiagnosed in the early stages, increasing the risk of liver failure and morbidity. Rarely post caesarean patient may present in shock condition mimicking either pulmonary embolism or reactionary haemorrhage.

HELLP syndrome has been classified into three classes;
Class I
The platelet count has been found to be moderately predictive of severity: under 50 m illion/L. This is the most severe condition.
class II
Platelet count is between 50 and 100. This condition is moderately severe.
class III
Platelet count is higher than100. The severity is mild.
To diagnose the disease, a group of blood tests is performed; a full blood count, liver enzymes, renal function and electrolytes and coagulation studies. Often, fibrin degradation products (FDPs) are determined, which can be elevated. Lactate dehydrogenase is a marker of hemolysis and is elevated more than 600 U/liter. Proteinuria is present, but can be mild.11
The only effective treatment is delivery of the baby. The DIC is treated with fresh frozen plasma to replenish the coagulation proteins, and the anemia may require blood transfusion. In mild cases, corticosteroids and antihypertensives such as labetalol, hydralazine & nifedipine may be sufficient. Intravenous fluids are generally required.

Dengue Fever.
Dengue fever and dengue hemorrhagic fever (DHF) are acute febrile diseases, found in the tropics.They are caused by one of four closely related virus serotypes of the genus Flavivirus, family Flaviviridae, each serotype is sufficiently different that there is no cross-protection and epidemics caused by multiple serotypes can occur. Dengue is transmitted to humans by the Aedes aegypti & rarely by the Aedes albopictus mosquitoes.12 This mosquitoes tends to bite just after dawn and just before sunset .
The signs & symptoms of the disease includes a sudden onset of fever, severe headache, muscle and joint pains and rashes. The dengue rash is characteristically bright red patch and usually appears first on the lower limbs and the chest. There may also be gastritis with some combination of associated abdominal pain, nausea, vomiting or diarrhea.
Patients with dengue can only pass on the infection through mosquitoes or blood products while they are still febrile.
The classic dengue fever lasts about six to seven days. Clinically, the platelet count will drop until the patient’s temperature is normal. Cases of DHF also show higher fever, haemorrhagic phenomena, thrombocytopenia and haemoconcentration. A small proportion of cases lead to dengue shock syndrome (DSS) which has a high mortality rate. Weak rapid pulse & narrow pulse pressure less than 20 mm Hg are the features of DSS.
The mainstay of treatment is supportive therapy. The patient is encouraged to keep up oral intake, especially of oral fluids. If the patient is unable to maintain oral intake, supplementation with intravenous fluids may be necessary to prevent dehydration and significant hemoconcentration. A platelet transfusion is rarely indicated if the platelet level drops significantly or if there is significant bleeding. But the transfusion is recommendable on platelet count falling below 20,000 without hemorrhage / bleeding or approx 50,000 with hemorrhage/bleeding.12
It is very important to avoid Aspirin and non-steroidal anti-inflammatory medications. Because in this case, they may actually aggravate the bleeding tendency associated with some of these infections.

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.13 It arises from a qualitative or quantitative deficiency of von Willebrand factor (vWF), a multimeric protein that is required for platelet adhesion. There are three types of hereditary vWD, but other factors such as ABO blood group may also play a part in the cause of the condition.13
The various types of vWD present with varying degrees of bleeding tendency. Severe internal or joint bleeding is rare, bruising, nosebleeds, heavy menstrual periods in women and blood loss during childbirth (rare) may occur. Death may also occur.
When suspected, blood plasma of a patient needs to be investigated for quantitative and qualitative deficiencies of vWF.14 Other tests performed in any patient with bleeding problems are a full blood count (especially platelet counts), APTT (activated partial thromboplastin time), prothrombin time, thrombin time and fibrinogen level.14 Testing for factor IX may also be performed if hemophilia B is suspected. Other coagulation factor assays may be performed depending on the results of a coagulation screen.14
Patients with vWD normally require no regular treatment. 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.15Mild cases of vWD can be trialled on desmopressin 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.

References.
1 Paula L. Bockenstedt & Alvin H. Scamaier, Platelet Function Disorders, Alvin H. Scamaier, Haematology For Medical Students.
2 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=40336
3 http://www.pnas.org/cgi/content/abstract/251543298v1
4 William F. Ganong, Review of Medical Physiology, 22nd ed, Lange Medical Publications: 1989.p.531
5 Bussel J, Kuter D, George J, McMillan R, Aledort L, Conklin G, Lichtin A, Lyons R, Nieva J, Wasser J, Wiznitzer I, Kelly R, Chen C, Nichol J (2006). “AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP”. N Engl J Med 355 (16): 1672- 81.
6 Tsai H (2003). “Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura”. J Am Soc Nephrol 14 (4): 1072-81.
7 Howard C, Adams L, Admire J, Chu M, Alred G (1997). “Vancomycin-induced thrombocytopenia: a challenge and rechallenge”. Ann Pharmacother 31 (3): 315-8.
8 Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. Mutations in the Glucocerebrosidase Gene and Parkinson’s Disease in Ashkenazi Jews. N Engl J Med 2004;351:1972-1977.
9 Barranger JA, Rice EO. Gaucher disease: diagnosis, monitoring and management. Gaucher Clin Persp 1997;5:1-6.
10 Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 1982;142:159-67.
11 Padden MO. “HELLP Syndrome: Recognition and Perinatal Management.” Am Fam Physician. 1999 Sep 1;60(3):829-36, 839.
12 Gubler D (1998). “Dengue and dengue hemorrhagic fever”. Clin Microbiol Rev 11 (3): 480-96.
13 Sadler, J. E. “Biochemistry and Genetics of von Willebrand factor.” Annu Rev Biochem 1998; 67:395-424.
14 Laffan m. Brown S. etal. The diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors Organisation. Haemophilia; 2004, 10, 199-217
15 Mannucci PM. Treatment of von Willebrands disease. N Engl J Med 2004;351:683- 94.

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