What Types of Hand Stereotypies are Associated with Rett Syndrome?

Patient Presentation
A pediatrician was having a conversation with her high school son who said that in his English class they were about to start reading Shakespeare’s MacBeth. “Oh, that’s a great play,” she said. “Why do you think so?” he asked. “Well any play that starts out with witches is bound to be mysterious. Shakespeare wrote great characters who are terribly flawed,” she answered. “Plus, whenever I think about it, I think about the famous scene where Lady MacBeth washes her hands and that reminds me of a very nice family I took care of. Their daughter had a problem called Rett Syndrome. In Rett Syndrome the girls wring their hands and unfortunately also have other disabilities. Whenever I think of this play, I think of them and wonder how they are doing. It also usually inspires me to review a little bit about Rett Syndrome too,” she added.

Discussion
Lady MacBeth and patients with Rett Syndrome (RS) are obviously not alike other than in making similar hand motions. In Shakespeare’s MacBeth (5.1.25-30), Lady MacBeth was driven into madness because of her murderous guilt and tries to wash the blood off her hands as she sleepwalks.

Doctor. What is it she does now? Look, how she rubs/ her hands.
Gentlewoman. It is an accustomed action with her, to seem thus/ washing her hands. I have known her continue in this/ a quarter of an hour.

In 1954, Dr. Andreas Rett observed 2 girls who were also making repetitive handwashing motions and later published a case series in 1966.

RS is a neurodevelopmental disorder caused by an X-linked dominant single gene deletion or mutation. The gene is the MECP2 gene which encodes for an epigenetic regulator protein called methyl-CpG protein 2 (MeCP2). Its complete function is still be elucidated but is involved in neurosynapse development and maintenance. The protein is found ubiquitously in the body but in higher concentrations in the brain. MeCP2 is found especially during early development but is also found in adults.

RS primarily affects females with an estimated prevalence of 1:10,000-15,000. Males with the mutation have a phenotype with severe neonatal encephalopathy and early death, but some males do survive. Classic RS patients are females who develop normally until ~6-18 months and then have developmental regression, deceleration of head growth and microcephaly, and stereotypical hand movements. There is marked differences in the phenotype for an individual but patients often have communication problems (both expressive and receptive language), cognitive deficits (can be severe), repetitive behaviors (particularly of the hands but also head, legs, feet, body and of sounds) and other problems including autonomic nervous system problems (irregular heart rate and breathing patterns), seizures (~70%) and spasticity, kyphoscoliosis, growth problems, gastrointestinal problems, small feet and gait abnormalities. Treatments are being worked on including genetic treatments and the use of medications such as IGF-1, GABA reuptake inhibitors and phentoin.

Other neurodevelopmental problems with epigenetic dysregulation include Fragile X syndrome, Prader-Willi syndrome, Angleman syndrome and Kabuki syndrome. A differential diagnosis of involuntary movement disorders can be found here.

Learning Point
RS is usually grouped with autism spectrum disorders (ASD) as ASD individuals have problems with communication, impaired social interaction and repetitive or stereotypical behaviors.

Hand stereotypies for patients with RS are much more common and marked than patients with ASD. One study of 40 patients with hand stereotypies found only patients with RS exhibited handwashing. A study of 83 patients with RS found that joined hand stereotypies occurred 80% of the time with washing behaviors occurring in 75.9% of patients. Mouthing occurred in 21.7% and clapping in 14.5%. Separated hand stereotypies occurred in 60.2% of patients with mouthing (36.1%), tapping (30.1%), hand gazing (14.5%) and hair pulling (10.8%) being the most common. Others included pill rolling, hand twirling, one hand behind neck, twisting 2-3 fingers, flapping, movements likes castanets or movements similar to Spanish dancers.

The stereotypies are often described as “…continuous, repetitive, compulsive automatisms…” that occur only during wakefulness and disappear during sleep.

Questions for Further Discussion
1. Compare and contrast Fragile X syndrome, Prader-Willi syndrome, Angleman syndrome and Kabuki syndrome.
2. What is epigenetics?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Rett Syndrome and Developmental Disabilities.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Hagberg B, Hanefeld F, Percy A, Skjeldal O. An update on clinically applicable diagnostic criteria in Rett syndrome. Comments to Rett Syndrome Clinical Criteria Consensus Panel Satellite to European Paediatric Neurology Society Meeting, Baden Baden, Germany, 11 September 2001. Eur J Paediatr Neurol. 2002;6(5):293-7.

Temudo T, Oliveira P, Santos M, et. al.. Stereotypies in Rett syndrome: analysis of 83 patients with and without detected MECP2 mutations. Neurology. 2007 Apr 10;68(15):1183-7.

Goldman S, Temudo T. Hand stereotypies distinguish Rett syndrome from autism disorder. Mov Disord. 2012 Jul;27(8):1060-2.

Rangasamy S, D’Mello SR, Narayanan V. Epigenetics, autism spectrum, and neurodevelopmental disorders. Neurotherapeutics. 2013 Oct;10(4):742-56

Castro J, Mellios N, Sur M. Mechanisms and therapeutic challenges in autism spectrum disorders: insights from Rett syndrome. Curr Opin Neurol. 2013 Apr;26(2):154-9.

Nissenkorn A, Levy-Drummer RS, Bondi O, et.al.. Epilepsy in Rett syndrome–lessons from the Rett networked database. Epilepsia. 2015 Apr;56(4):569-76.

International Rett Syndrome Foundation History of Rett Syndrome. Available from the Internet at: https://www.rettsyndrome.org/document.doc?id=159 (cited 10/13/15).

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital

What Are Risk Factors for Cholelithiasis?

Patient Presentation
An 18-year-old female came to clinic for weight management after having a cholecystectomy 5 months previously. She was now walking 3-4 days a week and had improved some of her eating habits. The past medical history showed that she had always been at the high end of the body mass index (BMI), but after puberty had dramatically put on weight and was up to a BMI of 44. Over the previous year she had intermittent abdominal pain that 5 months ago had become acute and she was evaluated in the emergency room where she was diagnosed with acute cholecystitis. She was admitted and several days later had a cholecystectomy. The pathology reported cholesterol stones.

The pertinent physical exam showed an obese female with a BMI of 40.1. Blood pressure was 132/84. She had a well healed scar in the upper right quadrant and abdominal striae. She had no acanthosis nigracans. The diagnosis of an obese female with improving BMI, status-post cholecystectomy was made. The physician applauded her efforts and they discussed ways that she could continue to slowly lose weight including a referral to a dietician that she had previously rejected seeing.

Discussion
Bile is produced by the liver to aid absorption of fat soluble vitamins and lipids from the gastrointestinal tract and to transport bilirubin, cholesterol and other substances to the gastrointestinal tract. Bile is the main form of cholesterol excretion. Gallstones or cholelithiasis form when the balance of substances within the hepatobiliary tract favors supersaturation with crystal formation and gallstone formation. It is a dynamic state of affairs as gallstones can form and also have a high rate of resorption of up to 50%. Gallstones 3 mm are called gallstones.

Gallstones, while not as common as adult population (15-20%), do occur in the pediatric population. A prevalence rate of 0.13-0.22% is often quoted. The prevalence increases up to 1.9% in a study from the Netherlands that used ultrasound screening. Infants and adolescents have the highest risk creating a bimodal distribution.

Patients can be asymptomatic (~33% for pediatrics vs 80% for adults) or symptomatic. Those that are symptomatic may not have the classic presentation of emesis, abdominal pain, fever and leukocytosis. Children can present with different problems including nausea and vomiting, jaundice, fatty food intolerance, acholic stools and fever. The abdominal pain may be generalized or more specifically attributable to biliary colic. Murphy’s sign or pain causing inspiration cessation when the gallbladder is palpated is helpful if present but can be difficult to illicit or determine in the pediatric age group.

There are 4 types of gallstones:

  • Cholesterol stones
    • An increased cholesterol relative to bile salts creates supersaturated cholesterol stones
    • Constituent – 70% cholesterol and 30% other constituents including also bilirubin, protein, calcium carbonate
    • Increased incidence and prevalence because of increasing obesity
  • Black pigment stones
    • Increased unconjugated bilirubin and calcium forms the stones
    • Constituent – calcium bilirubinate
    • Usually due to increased hemolysis
    • Occurs in 20-40% of children with gallstones
  • Brown pigment stones
    • Increased fatty acid and calcium forms the stones
    • Constituent – calcium bilirubinate and fatty acids
    • Associated with infection, either bacterial or helminthic, in the biliary tract
    • Rare in children
  • Calcium carbonate stones
    • Possibly due to cystic duct narrowing which allows calcium salts to precipitate
    • Constituent – calcium salts
    • Only seen in children

Laboratory evaluation includes liver enzymes (AST, ALT, GGT), bilirubin and alkaline phosphatase, amylase, and a complete blood count. These tests can be normal even in acute cholecystitis. Transabdominal ultrasound is usually the initial imaging test. Gallstones may be detected as echogenic shadows in the gallbladder and potentially the common bile duct (although that can be difficult to detect). Evaluation of the size of the bile duct and also the pancreas can also be done by ultrasound. Endoscopic retrograde cholangiopancreatography (ERCP) is helpful both diagnostically and therapeutically.

Treatment includes monitoring (especially because of high rate of resolution for many patients), medications to help dissolve the stones including ursodeoxycholic acid which can be very helpful for cholesterol stones, extracorporeal shock-wave lithotripsy, cholcystolithotomy (removal of stones but gallbladder is left in-situ) or cholecystectomy. Cholecystectomy is often used for patients with black pigment stones particulary caused by sickle cell anemia. Patients with sickle cell disease are more likely to have acute cholecystitis and to have complications related to cholecystectomy at the time of acute cholecystitis. Therefore once gallstones are detected in patients with sickle cell disease, prophylactic cholecystectomy should be discussed.

Learning Point
Risk factors for gallstones include:

  • Hemolytic disease – sickle cell anemia, thalassemia, glucose-6-phosphate deficiency, hereditary spherocytosis, Gilbert syndrome
  • Parenteral nutrition
  • Systemic infection
  • Necrotizing enterocolitis
  • Antibiotic use – particularly ceftriaxone
  • Anatomic abnormalities of the hepatic/pancreatic system and also terminal ileum (i.e. Crohn’s disease)
  • Obesity
  • Genetic – Cystic fibrosis, Native American, Mexican American
  • Increased estrogen state – pregnancy, oral contraceptives, post-pubertal female
  • Prematurity
  • Congenital heart disease and heart transplant
  • Surgery – Bowel resection and cardiac bypass

Questions for Further Discussion
1. What is a sonographic Murphy sign?
2. What should be included in the differential diagnosis of right upper quadrant pain?
3. What are complications of cholelithiasis?
4. What is the differential diagnosis of abdominal pain? See here for abdominal pain or recurrent abdominal pain

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Gallstones and Obesity.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Poddar U. Gallstone disease in children. Indian Pediatr. 2010 Nov;47(11):945-53.

Poffenberger CM, Gausche-Hill M, Ngai S, Myers A, Renslo R. Cholelithiasis and its complications in children and adolescents: update and case discussion. Pediatr Emerg Care. 2012 Jan;28(1):68-76.

Svensson J, Makin E. Gallstone disease in children. Semin Pediatr Surg. 2012 Aug;21(3):255-65.

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital

Why Is It Called Christmas Disease?

Patient Presentation
An 4-year-old male came to clinic in December for his well child care. He was known to have Factor IX deficiency after he had spontaneous bleeding into an elbow as a toddler. He was receiving prophylactic factor treatment at the regional children’s hospital. The past medical history showed no other major bleeding episodes. The family history was negative for other bleeding problems and it appeared that this was a spontaneous mutation.

The pertinent physical exam showed normal vital signs and growth parameters were approximately 75%. His examination was normal including a detailed joint examination. The diagnosis of a preschooler with Factor IX deficiency was made. After seeing the patient the attending remarked to the resident that there were a couple of other names for this disease including Christmas disease. “I can’t remember exactly why, but that is one name that I always remembered from medical school and it’s kind of appropriate for this time of year too,” she remarked.

Discussion
Too much or too little causes the important homeostatic balance of life to be upset. This is true of the interactions between the circulatory and hematology systems of the body and their important function in ensuring that the circulatory system plumbing is not leaking (i.e. bleeding) and also not getting plugged up (i.e. thrombosis). A healthy system has adequate numbers of functional platelets, and protein synthesis of the factors needed for a balanced hemostasis system. An adequate amount of Vitamin K is needed for some factors activity. Additionally the absence of any drugs that interfere with platelets or the factors (i.e. aspirin, heparin, warfarin, etc.) is needed for a healthy system.

If any one of the clotting cascade factors is missing or abnormal, then bleeding can result. Hemophilia A, Hemophilia B and von Willebrand Disease are the most common bleeding disorders with von Willebrand Disease being the most common inherited bleeding disorder overall.

The coagulation cascade is naturally a highly regulated system with many parts that is usually divided into 2 pathways that activate a common pathway. Images of the coagulation cascade can be reviewed here.
The factors involved are:

Intrinsic system – VIII, IX, X, XI, XII
Extrinsic system – III, VII
Common pathway – I, II, V, X, XIII
Factors that are dependent on Vitamin K for activity are – II, VII, IX and X, plus Protein C, Protein S and Protein Z which are regulator proteins

Most of the problems with the factors fall into one of three categories: not produced (e.g. afibrinogenemia), produced but in inadequate quantities for appropriate clotting (e.g. hypofibrinogenemia), produced but the protein is abnormal and does not function properly (e.g. dysfibrinogenemia).

  • Factor I – Fibrinogen
    • Fibrinogen is enzymatically changed to fibrin which stabilizes the platelet plug.
    • Identified in 1920 by German physicians
    • Rare, may be autosomal recessive or autosomal dominant
    • Umbilical cord or circumcision bleeds, mucous membrane or tissue bleeding, joint and muscle bleeding, childbirth bleeding and also infertility because of embryo implantation problems
    • Testing with PT, aPTT, thrombin clotting time and fibrinogen
    • Treatment with factor concentrate, fresh frozen plasma or cryoprecipitate

  • Factor II – Prothrombin
    • This is the precursor of thrombin which enzymatically changes fibrinogen to fibrin
    • Identified in 1947 by Dr. A. Quick
    • Autosomal recessive or acquired
    • Bruising, nosebleed, umbilical cord bleeding, menorrhagia, hemorrhage after trauma, surgery or childbirth. Joint bleeds are rare
    • Diagnosed with PT and aPTT testing, prothrombin
    • Vitamin K dependent
    • Treatment with prothrombin concentrates or fresh frozen plasma

  • Factor III – Tissue Factor
    • Glycoprotein on the subendothelium that activates the extrinsic system.

  • Factor IV – Calcium

    • Factor V – Proaccelerin, Labile Factor, Owren’s Disease or Parahemophilia
      • Accelerator of conversion of prothrombin to thrombin
      • Described in one patient in 1943, and also by Dr. P. Owren in 1947
      • Autosomal recessive
      • Skin, mucous membrane, menorrhagia, infants may have intracranial bleeding
      • Diagnosed by PT, aPTT, thrombin clotting time and factor assay
      • Treatment by fresh frozen plasma
      • Rarely can have combined Factor VIII and Factor V deficiency

    • Factor VI – Activated form of Factor V

      • Factor VII – Labile Factor, Proconvertin, Alexander’s Disease
        • Helps to activate and regulate Factor X
        • Identified in 1951
        • Autosomal recessive
        • Joint and muscle bleeding, bruising and bleeding after surgery, infants may have intracranial bleeding
        • Testing is by aPTT and PT and by factor assay
        • Vitamin K dependent
        • Treatment is by recombinant factor and prothrombin complex concentrates and sometimes fresh frozen plasma

      • Factor VIII – Hemophilia A or Classic Hemophilia
        • Helps to regulate the intrinsic system by activation of Factor IX
        • Identified in 1953 by Alexander and Goldstein
        • X-linked recessive with ~1/3 patients with spontaneous mutation
        • Mild Hemophilia A has factor levels of 6-30% and occurs in about 25% of patients, often have bleeding after serious trauma or surgery, may have menorrhagia or postpartum bleeding
        • Moderate Hemophilia A has factor levels of 1-5% and occurs in 15% of patients, often have bleeds after injuries and may have spontaneous bleeding
        • Severe Hemophilia A has factor levels of < 1% and occurs in about 60% of patients, often has frequent spontaneous bleeding into muscles and joints
        • Testing through PTT with normal PT and bleeding time along with factor assay
        • Treatment is with recombinant factor, DDAVP and antifibrinolytic agents are also being used
        • Preventive treatment with recombinant factor is often given

      • Factor IX – Christmas Disease or Royal Disease
        • Helps to regulate the intrinsic system by activation of Factor X
        • 1953 – see more below
        • X-linked recessive with about 1/3 of patients with spontaneous mutation
        • Patients with Factor IX deficiency tend to bleed longer than other people
        • Mild Hemophilia B has factor levels of 6-30% and occurs in about 25% of patients, often have bleeding after serious trauma or surgery, may have menorrhagia or postpartum bleeding
        • Moderate Hemophilia B has factor levels of 1-5% and occurs in 15% of patients, often have bleeds after injuries and may have spontaneous bleeding
        • Severe Hemophilia B has factor levels of < 1% and occurs in about 60% of patients, often has frequent spontaneous bleeding into muscles and joints
        • Testing with PT, aPTT and factor assay
        • Treatment with recombinant factor and antifibrinolytics
        • Preventive treatment with recombinant factor is often given

      • Factor X – Stuart – Prower Factor
        • Clotting enzyme activation, the key factor for thrombin production
        • Named for 2 patients in the 1950s
        • Autosomal recessive
        • Mucous membrane bleeding or bleeding after surgery. Can also have joint bleeding, CNS or GI bleeding, menorrhagia, may have increased miscarriages
        • Vitamin K dependent
        • Testing through PT, PTT, aPTT and factor assay
        • Treatment is by fresh frozen plasma, prothrombin complex concentrates. Antifibrinolytic agents can be used for mild symptoms

      • Factor XI – Hemophilia C, Rosenthal Syndrome, Plasma Thromboplastin Antecedent Deficiency
        • Regulates the clotting cascade and increases amount of thrombin
        • Identified in 1953
        • Autosomal recessive
        • Identified initially in patients who bleed after dental surgery, also mucous membrane bleeding, bleeding after surgery or trauma, menorrhagia and postpartum bleeding
        • Testing is by PT, aPTT and bleeding time, platelet function tests, and factor assay
        • Treatment is by factor concentrates in some countries, fresh frozen plasma and antifibrinolytics along with fibrin glue for some types of bleeding.

      • Factor XII _ Hageman Factor
        • Activates Factor XI to generate thrombin
        • Identified by John Hagemen in 1955
        • Autosomal recessive
        • Problems with poor wound healing, generally do not have bleeding itself
        • Testing by prolonged aPTT and factor analysis
        • Treatment – none needed

      • Factor XIII – Fibrin Stabilizing Factor
        • Stabilizes blood clots, without it clot forms but disintegrates
        • Identified in 1960
        • Rarest factor deficiency
        • Autosomal recessive
        • Umbilical cord bleeding is most common, mucous membrane bleeding, muscle and CNS bleeding, delayed bleeding after surgery
        • Testing by factor analysis and clot solubility testing
        • Treatment by specific Factor XIII products

      • von Willebrand Factor
        • Carrier for Factor VIII, platelets and blood vessels and helps form clot
        • Identified by Erik von Willebrand in the 1920s
        • Autosomal dominant or Autosomal recessive
        • Mucous membrane bleeding, bleeding after surgery, childbirth and menorrhagia
        • Type 1 due to quantitative problem in the protein with levels that are 20-50% of normal, occurs in 60-80% of patients, symptoms are mild
        • Type 2 have a qualitative problem in the protein and occurs in 15-30% of patients, symptoms are mild to moderate
        • Type 3 due to quantitative problem in the protein with severe symptoms
        • Acquired due to medications or illnesses such as cancer or lupus
        • Testing by factor assay
        • Treatment is by DDAVP, antifibrinolytic agents and factor concentrate

      Learning Point

      Hemophilia B is called Christmas Disease because it was named for a 5 year old boy named Christmas. He was the first patient described in a case series of 7 patients by Biggs et. al. in 1953. “He had numerous episodes of haemorrhage dating from the age of 20 months, mostly resulting from injuries during play. He was transfused on numerous occasions; each transfusion resulted in abrupt cessation of bleeding.”

      Hemophilia B is called sometimes called Royal Disease because hemophilia was known to be transmitted among the European royal families who were descendants of Queen Victoria of the United Kingdom. One of Queen Victoria’s granddaughters’ Alexandra became Czarina of Russia. Her son Crown Prince Alexei was the only son and heir of the Czar and was affected by hemophilia since infancy and had severe bleeding episodes. As there was no effective treatment at the time, Alexandra looked for many types of treatment including her own religious faith and spiritualists. One of these was the faith healer Grigori Rasputin that she believed did provide some help to Alexei. “According to some historians, when Rasputin used his close relationship with the Romanovs [surname of the Czar and Czarina] to influence bureaucratic affairs in his favor, the public grew increasingly suspicious of the regime, possibly hastening the [Russian] revolution [of 1917].” The Czar and his family were eventually executed in 1918.

      In 2009, scientists using bone samples from the Romanov family remains determined that their hemophilia was a severe form of Hemophilia B caused by an abnormal splicing site in the F9 gene of the X chromosome. The last carrier of Royal Disease who died in 1945 was Prince Waldemar of Prussia.

      While Queen Victoria and Christmas Disease are linked, it interesting to note that her consort Prince Albert is often recognized as importing many Christmas traditions such as lighted Christmas trees from his native Germany to the United Kingdom. These traditions in turn were spread to other predominantly English-speaking countries initially and today many are global.

      Questions for Further Discussion
      1. How has AIDS and HIV affected patients with bleeding disorders?
      2. How do inhibitors affect people with bleeding disorders?

      Related Cases

      To Learn More
      To view pediatric review articles on this topic from the past year check PubMed – Hemophilia A and PubMed – Hemophilia B.

      Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

      Information prescriptions for patients can be found at MedlinePlus for these topics: Hemophilia and Bleeding Disorders.

      To view current news articles on this topic check Google News.

      To view images related to this topic check Google Images.

      To view videos related to this topic check YouTube Videos.

      Biggs R, Douglas AS, Macfarlane RG, Dacie JV, Pitney WR, Merskey C, O’Brien JR. Christmas disease: a condition previously mistaken for haemophilia. Br Med J. 1952 Dec 27;2(4799):1378-82.

      Case Closed: Famous Royals Suffered From Hemophilia. Science Magazine. Available from the Internet at http://news.sciencemag.org/biology/2009/10/case-closed-famous-royals-suffered-hemophilia (rev. 10/8/2009, cited10/5/15).

      Rogaev EI, Grigorenko AP, Faskutdinova G, Kittler ELW, Moliaka YK. Genotype Analysis Identifies the Cause of the “Royal Disease”. Science. 6 November 2009:326(5954);817.

      Giordano P, Franchini M, Lassandro G, Faienza MF, Valente R, Molinari AC. Issues in pediatric haemophilia care. Ital J Pediatr. 2013 Apr 20;39:24.

      Fischer K, Konkle B, Broderick C, Kessler CM. Prophylaxis in real life scenarios. Haemophilia. 2014 May;20 Suppl 4:106-13.

      Ljung R, Gretenkort Andersson N. The current status of prophylactic replacement therapy in children and adults with haemophilia. Br J Haematol. 2015 Jun;169(6):777-86.

      British Broadcasting Company. Victorian Christmas – History of Christmas.
      Available from the Internet at http://www.bbc.co.uk/victorianchristmas/history.shtml (cited 10/5/15).

      King M. Introduction to Blood Coagulation. Available from the Internet at http://themedicalbiochemistrypage.org/blood-coagulation.php (rev. 6/23/15, cited 10/6/15).


      National Hemophilia Foundation. Types of Bleeding Disorders. Available from the Internet at https://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders (rev. 2015, cited 10/5/15).

      Author
      Donna M. D’Alessandro, MD
      Professor of Pediatrics, University of Iowa Children’s Hospital