Hemophilia

Hemophilia is a congenital bleeding disorder that results in the blood failing to clot normally.  It is caused by a deficiency of a protein in the blood called a clotting factor. People with hemophilia bleed easily and often excessively. Untreated, hemophilia can be life-threatening. There are two main types of hemophilia: “Hemophilia A” is the most common type and is caused by the deficiency of what is known as Clotting Factor VIII; “hemophilia B” is caused by deficiency of Clotting Factor IX.

Hemophilia occurs in about 1 in 10,000 births and it is much more common in males because it is an “X-linked” disorder. The number of affected persons worldwide is estimated to be about 400,000. Hemophilia A is more common than hemophilia B, representing 80-85% of all cases.

Diagnosis

Hemophilia should be suspected in patients presenting with a history of:

• Easy bruising in early childhood.
• Spontaneous bleeding (bleeding for no apparent/known reason), especially into the joints, muscles, and soft tissues.
• Excessive bleeding following trauma or surgery.

A definitive diagnosis depends on a blood analysis to determine deficiency of Clotting Factor VIII or IX.

Because each type of Hemophilia requires a different therapy, accurate diagnosis is essential.

Therapy

Hemophilia can be very successfully managed by simply replacing the deficient clotting factor. Therapy can be either “on demand” – the treatment of active bleeding, or “prophylactic” – regular maintenance of clotting factor levels to prevent bleeding. In developed countries where these factors are readily available, the life expectancy of males suffering from Hemophilia is essentially the same as for males in the general population.
Both clotting factors can be isolated from donated human plasma and they can also be engineered by means of recombinant DNA technology.  There are many commercial brands from which to choose and that choice is generally made based on availability, access, price and on the risk of developing antibodies that render the factor ineffective.

References:

Srivastava A. et al. Guidelines for the management of Hemophilia. Haemophilia (2012), 1–47.

Mannucci PM et al. How we choose factor VIII to treat Hemophilia. Blood (2012) volume 119, number 18, 4108-4114

The most common bleeding disorder is von Willebrand disease (VWD).  It is congenital and caused by deficiency or abnormality in a plasma protein central to blood clotting known as the von Willebrand Factor (named after the Finnish physician who first identified the disorder).

Von Willebrand Factor (VWF) is the “glue” that helps platelets in the blood stick together with the vessel wall, to form a clot where a blood vessel has been ruptured. It also binds and stabilizes the clotting factor Factor VIII, so in patients with VWD, the lack of VWF activity results in premature elimination of Factor VIII in the circulation, thereby resulting in a dual defect in the body’s ability to stop bleeding. People with VWD produce normal amounts of Factor VIII, but with deficient VWF the clotting factor does not stay in the system long enough to adequately carry out its function, as in patients with type 1 and III VWD.

There are three generally recognized forms of the disease:

• Type I: The most common and mildest form of Von Willebrand Disease. Levels of von Willebrand Factor are lower than normal, and levels of Factor VIII may also be reduced.
• Type II:  In this form of Von Willebrand Disease, there is normal and sufficient Von Willebrand Factor but it is abnormal and does not work properly. The abnormality in the factor can vary and accordingly there are several subtypes of Type II Von Willebrand Disease – important to determine because treatment varies with the subtype.
• Type III: The most severe form of Von Willebrand Disease in which VWF is nearly or completely absent along with very low levels of Factor VIII.

People with Von Willebrand Disease can bruise easily; suffer frequent nosebleeds that can be difficult to stop; have heavy menstrual bleeding; and experience heavier and longer than normal bleeding after injury, surgery, childbirth, or dental work. In its most severe form, it can lead to spontaneous joint and organ bleeding and can be life-threatening.

Some patients respond favorably to injection of desmopressin acetate (DDAVP) but the most effective treatment and prophylaxis for VWD – especially in its more severe forms – is therapy with plasma-derived Von Willebrand Factor products.

References:

Federici AB. Classification and clinical aspects of von Willebrand disease. In: Textbook of Haemophilia 2nd Edition, Lee CA, Berntorp E, Hoots K (eds). Oxford: Wiley-Blackwell 2010. 302–308.

Immune System Disorders

Disorders of the Immune System fall generally in three categories:

• Overactive or inappropriate immune response.
• Deficient immune response.
• Autoimmune (self-attacking) response.
• Asthma and allergies are examples of an overactive immune system reacting to a non-threatening foreign substance.
• Immune deficiencies (Immunodeficiencies) and autoimmune disorders are generally more serious and can be life-altering.

Immunodeficiencies

When one of the parts of the immune system is missing or does not work well, we say that the immune system is deficient. Most often this involves missing or defective T- or B-lymphoctyes or inadequate production of antibodies. The result is that the body is vulnerable to infections that might otherwise be easily defeated.

Immunodeficiencies can be “Primary”, i.e., present at birth and usually genetic, or “Secondary”. Secondary Immunodeficiencies have many causes, including disease, malnutrition, aging, certain medications, chemo- and radiation therapy, and stress.  Probably the most well-known cause of immunodeficiency, though not the most common, is the Human Immunodeficiency Virus (HIV), which can cause AIDS (Acquired Immune Deficiency Syndrome).

There are some 185 Primary Immunodeficiencies recognized by the World Health Organization.  Most common are those involving the production of antibodies and are called Primary Antibody Deficiencies (PAD’s).  These disorders vary greatly in their underlying defects, but many of them can be managed and their symptoms mitigated by regular infusions of Immunoglobulin.

Kedrion’s ongoing research and development has resulted in several Immunoglobulin therapies for these conditions. Replacement therapy with Immunoglobulin in Primary Antibody Deficiencies increases life expectancy and reduces infection frequency and severity.

References:

Abbas K. et al. “Le basi dell’Immunologia. Fisiopatologia del sistema immunitario”. Ed. Masson Elsevier 2006.

Autoimmune Diseases

The human body can sometimes become its own worst enemy. For reasons still not fully understood the human immune system can lose some of its ability for distinguishing between self and non-self and begin attacking normal healthy cells in the body.  This is a condition known as Autoimmune Disease.

There are many Autoimmune Diseases that affect millions of people and their incidence seems to be growing worldwide.

The following Autoimmune Diseases are ones for which intravenous Immunoglobulin (IVIg) therapy is indicated and approved:

• Idiopathic Thrombocytopenic Purpura (ITP).  Also known as Immune Thrombocytopenic Purpura or Autoimmune Thrombocytopenic Purpura, ITP is an autoimmune bleeding disorder resulting when the immune system attacks its own blood platelets, which are important to the clotting process.  For reasons not well understood, lymphocytes produce antibodies that attach to the platelets, which then do not clot effectively and are subsequently recognized as “foreign” and destroyed in the spleen. Frequent and abnormal bleeding is typical and often results in many small bruises that can look like a rash (purpura). Children are generally affected with an acute form of the disorder that resolves spontaneously in a few months while in adults it is usually a chronic condition requiring long term treatment.  The disease is rare, with an incidence of 3 cases per 100,000 inhabitants per year in those aged under 16 years and 1.6 to 2.68 cases per 100,000 inhabitants per year in adults, with a slight female preponderance.
• References:

Navarro RP et al.; Considerations for the Optimal Use of Immunoglobulin. Am J Manag Care. 2012;18:S67-S78

Abrahamson PE. The incidence of idiopathic thrombocytopenic purpura among adults: a population-based study and literature review. Eur J Haematol..2009 Aug;83(2):83-9.

• Kawasaki Disease.  Also known as Mucocutaneous Lymph Node Syndrome, is a form of vasculitis characterized by inflammation of blood vessels throughout the body. It primarily affects children under the age of five (and rarely over the age of eight).
  With proper treatment the prognosis for these children is good, but without treatment about a quarter of them will develop cardiac problems, including coronary artery aneurysms. Kawasaki Disease has become the leading cause of acquired heart disease in children in the developed world.
  The cause of Kawasaki Disease is still unknown with researchers divided on whether it is an infection or an autoimmune response, but effective treatment includes Primarily Intravenous Immunoglobulin.
• References:

Uehara R, Belay ED. “Epidemiology of Kawasaki disease in Asia, Europe, and the United States” J Epidemiol 2012; 22 (2): 79-85

Takahashi K et al.; Pathogenesis of Kawasaki disease. Clinical and Experimental Immunology, 2011; 164 (Suppl. 1): 20–22

Newburger JW. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics. 2004;114:1708–1733

Guillain-Barré Syndrome

This is a rare (affecting just 1-2 people in 100,000) Autoimmune Disease in which the immune system attacks the myelin or outer covering of nerves (and sometimes the nerves themselves) of the Peripheral Nervous System.  The damage leads to tingling and weakness in the legs and can proceed to even life-threatening paralysis.

Symptoms generally reach their most severe within days or weeks when they stabilize for a period of days, weeks or even months.  Most people recover from even the most severe cases, but recovery can take as little as a few weeks or as much as a few years.  The cause of the autoimmune response is unknown but it is sometimes triggered by infection, surgery or vaccination.

One treatment for Guillain-Barré syndrome that can reduce symptoms and hasten recovery is high dose Immunoglobulin therapy.

Chronic Inflammatory Demyelinating Polyneuropathy

CIDP can be thought of us a chronic form of the Autoimmune Disorder Guillain-Barré syndrome caused by demyelination of peripheral nerves, resulting in loss of sensation, motor weakness, and sensory symptoms.

Its estimated prevalence ranges from 0.8 to 8.4 per 100,000 people. CIDP is often disabling with over 50% of patients having temporary disability and about 10% eventually becoming persistently disabled or dying because of the disease.

The cause of CIDP remains unknown, but there are data supporting an immune pathogenesis. Plasmapheresis (plasma exchange), oral corticosteroids and Intravenous Immunoglobulin (IVIg) therapy are effective treatments, but should be started early to avoid permanent nerve damage.

References:

Pithadia AB et al.; Guillain-Barre syndrome (GBS). Pharmacological Report 2010; 62: 220 – 232

Köller H et al.; Chronic inflammatory demyelinating polyneuropathy. N Engl J Med.2005 Mar 31;352(13):1343-56.

Mahdi-Rogers M et al.; Overview of the pathogenesis and treatment of chronic inflammatory demyelinating polyneuropathy with intravenous immunoglobulins. Biologics. 2010 Mar 24;4:45-9.

E. Nobile Orazio. Intravenous immunoglobulin versus intravenous methylprednisolone for chronic inflammatory demyelinating polyradiculoneuropathy: a randomised controlled trial. Lancet Neurol 2012; 11 (6): 493-502

Maternal-fetal red cell antigen incompatibility can lead to alloimmunization, maternal Immunoglobulin transplacental transfer, and Hemolytic Disease of the Fetus and Newborn (HDFN).

Hemolytic Disease of the Fetus and Newborn (HDFN), also called Erythroblastosis Fetalis, is a condition that can arise when a mother and her unborn child have different and incompatible blood types. If even a few of the fetus’s red blood cells cross over the placenta and get into the mother’s circulation during the pregnancy, they are recognized by her immune system as “foreign” and it will produce antibodies to attack them. If these antibodies cross back over into the fetus, they will begin to destroy fetal red blood cells.

Since it takes time for antibodies to develop, the first child might not be seriously affected, but the mother’s immune system will now be sensitized to these incompatible red blood cells and subsequent pregnancies involving similar incompatibility will be seriously threatened.

The most serious type of HDFN is the one caused by Rh incompatibility in which the mother has Type Rh Negative blood and the fetus, Rh Positive. Although HDFN can be extremely serious, it is rare and preventable.

Passive Immunization with anti-D antigen Immune Globulin protects Rh(D)-negative women from sensitization against Rh(D)-positive red blood cells.
The use of Routine Antenatal Anti-D Prophylaxis (RAADP) has sharply decreased the incidence of and mortality from HDFN due to RhD allosensitization. However, despite the advent of anti-Rh(D) immunoglobulin prophylaxis, severe morbidity and death because of Rh disease have only been reduced by approximately 50% globally during the last 50 years.

References

Visser et al. The continuing burden of Rh disease 50 years after the introduction of anti-Rh(D) immunoglobin prophylaxis: call to action. Am J Obstet Gynecol. 2019 Sep;221(3):227.

Liumbruno et al. The role of antenatal immunoprophylaxis in the prevention of maternal-foetal anti-Rh(D) alloimmunisation. Blood Transfus 2010; 8:8-16

Bowman JM. Controversies in Rh prophylaxis: who needs Rh immune globulin and when should it be given? Am J Obstet Gynecol 1985; 151: 289-94.

Clarke CA, Donohoe WTA, McConnell RB, et al. Further experimental studies on the prevention of Rh haemolytic disease. Br Med J 1963; 1: 979-84.

Women HBV positive can transmit HBV to their babies. In areas endemic for HBV, such as Western Pacific Region and Africa, up to 20% of the general population is chronically infected, with perinatal/neonatal and childhood infections existing as a primary route for expanding the reservoir of carriers.

Chronic HBV infection, even if asymptomatic for decades, can result in eventual death from cirrhosis and hepatocellular carcinoma (HCC). Mother-to-child transmission of HBV has been associated with an increased risk of HCC. Consequently, in Asian and African countries with a high incidence of perinatal and early childhood infection, death from cirrhosis or HCC (more than half due to HBV infection) is common, among the top ten causes of death. Thus, from the outset, prevention of chronic infection in children has been a key component of HBV immunization strategies.

The currently recommended practice to reduce mother-to-child HBV vertical transmission relies on the administration of HBV vaccine and concurrent administration of hepatitis B immune globulin (HBIG) at the time of or shortly after birth. A small but growing body of data suggests that maternal treatment with NA therapy in the third trimester of pregnancy in addition to vaccine and HBIG for the infant may also reduce HBV transmission to the infant.

References

Silverman, N, Glob. libr. women’s med.,ISSN: 1756-2228) 2008; DOI 10.3843/GLOWM.10181.

Lee C., Gong Y., Brok J. et al. Effect of hepatitis B immunization in newborn infants of mothers positive for HBsAg: systematic review and meta-analysis, BMJ 2006;332:328-336

Beasley R.P. Rocks along the road to the control of HBV and HCC. Ann Epidemiology 2009;19:231-234 Red Book, current version 2018-2021

Guidelines For The Prevention, Care And Treatment Of Persons With Chronic Hepatitis B Infection, Who, March 2015

Chronic hepatitis B (CHB) caused by hepatitis B virus (HBV) infection remains a major global health problem affecting an estimated 350 million people worldwide with more than 786000 individuals dying annually due to complications of CHB, including cirrhosis and liver cancer. CHB is the leading cause of hepatocellular carcinoma (HCC) accounting for at least 50% of newly diagnosed cases. Furthermore, HCC is the third leading cause of cancer-related mortality in the world with a dismal 5-year survival and the fastest growing rate of cancer death in North America.

Liver transplantation (LT) is the most effective treatment in patients with CHB-related liver failure, cirrhosis and HCC. However, HBV reactivation following LT emerges as a major clinical challenge. Prophylaxis with high-dose hepatitis B immunoglobulin (HBIG) and anti-viral drugs have achieved remarkable progress in LT by suppressing viral replication and improving long-term survival.

Before its introduction, reinfection with HBV after transplantation occurred in more than 80% of recipients and the 5-year graft and patient survival rates were only 50%. Now, with the use of the HBIg/nucleoside/nucleotide analogue prophylaxis, transplant programs in North America and Europe can expect prevention of HBV recurrence in greater than 90% of their patients.

Hepatitis B is contagious, but it can be transmitted from mothers to infants at the time of birth. This transmission can be markedly reduced by the immediate postpartum administration of HBIg to the infant either alone or, as currently recommended, concomitant administration of hepatitis B vaccine.

References:

El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264–1273.e1. [PMC free article] [PubMed] [Google Scholar]

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Realdi G, Fattovich G, Hadziyannis S, et al. Survival and prognostic factors in 366 patients with compensated cirrhosis type B: a multicenter study. The Investigators of the European Concerted Action onViral Hepatitis (EUROHEP). J Hepatol 1994; 21: 656^666.

Arianeb Mehrabi, “The role of HBIg as hepatitis B reinfection prophylaxis following liver transplantation” Langenbeck’s Archives of Surgery June 2012, Volume 397, Issue 5, pp 697-710.

American Academy of Pediatrics. Hepatitis B. In: Peter G, editor. 1997 Red Book. Report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, Ill: American Academy of Pediatrics; 1997. pp. 247–260.

Albumin is the most abundant circulating protein in the human body, making up about 50% of the total plasma protein content.

Albumin has been the first plasmaprotein produced from human plasma for therapeutic use. The scientific evidence of recent years has clearly shown that albumin is endowed with a long series of clinically relevant functions: alongside the well-known oncotic power, albumin performs many other activities that are grouped under the definition of non-oncotic properties. These include : Binding , Transport and detoxification, Antioxidant action, Modulation of the inflammatory and immunological response, Antithrombotic action, Capillary permeability and endothelial stabilization, Adjustment of acid-base balance.

The oncotic activity, together with the long circulating half-life and total half-life make albumin an excellent plasma expander, which is currently the main reason for its use in clinical practice expecially in critical situations. The non-oncotic activities play an important therapeutic role in many medical conditions where the condition of deficient plasma volume is associated with a pro- inflammatory state as in liver cirrhosis, sepsi/septic shock, burns.

All these properties makes albumin an important medicine for many clinical conditions for which other fluids are either contro-indicated or have no important therapeutic effect.

References:

Quinlan GJ, Martin GS, Evans TW. Albumin: biochemical properties and therapeutic potential. Hepatology 2005; 41:1211–1219.

Fanali G, Di Masi A, Trezza V, et al. Human serum albumin: from bench to bedside. Mol Aspects Med 2012; 33: 209-90.

Vincent J-L, Russell JA, Jacob M, et al. Critical Care 2014;18:231-41

Garcia-Martinez R, Caraceni P, Bernardi M, Gines P, Arroyo V, Jalan R. Albumin: pathophysiologic basis of its role in the treatment of cirrhosis and its complications. Hepatology 2013; 58:1836-46.

Taverna M, Marie AL, Mira JP, Guidet B. Specific antioxidant properties of human serum albumin. Ann Intensive Care. 2013

Schött U, Solomon C, Fries D, Bentzer P. The endothelial glycocalyx and its disruption, protection and regeneration: a narrative review. Scand J Trauma Resusc Emerg Med. 2016 Apr 12;24:48.

Antithrombin is a plasma protein that inactivates Thrombin, a plasma enzyme that is important in the clotting process. Antithrombin therefore acts as a powerful anticoagulant and is used to treat acquired antithrombin deficiency from Disseminated Intravascular Coagulation (DIC) as the result of sepsis, multiple trauma, severe burns, pregnancy complications, extensive surgery, etc.

Antithrombin is also used in patients with congenital antithrombin deficiency for the prophylaxis of deep vein thrombosis and thromboembolism in clinical risk situations (especially during surgery or during the peri-partum period) and for the prevention of progression of deep vein thrombosis and thromboembolism in association with heparin, when indicated.

PCC is a complex of human plasma coagulation factors for treatment of bleeding and perioperative prophylaxis of bleeding in acquired prothrombin deficiency, when rapid correction of the deficiency is required.

PCC is also used for treatment of bleeding and perioperative prophylaxis in congenital deficiency of any of the vitamin K dependent coagulation factors when purified specific coagulation factor product is not available.

References:

Rita Garcia-Martinez. Albumin: Pathophysiologic Basis of Its Role in the Treatment of Cirrhosis and Its Complications. Hepatology, Month 2013

Afshari A. Antithrombin III for critically ill patients (Review). The Cochrane Library 2009, Issue 2

Sibylle A. Management of severe perioperative bleeding. Eur J Anaesthesiol 2013; 30:270–382

Rabies is a prolifically deadly zoonotic disease. Rabies-related human deaths are infrequent due to prophylaxis using vaccines and human rabies immunoglobulin (HRIG), providing nearly 100% success rates. Fatalities from rabies occurs when patients fail to seek medical attention. While this does not occur often, preventable deaths were reported within the last year.

Given the rarity of this disease and, therefore, the low incidence of cases reported in medical clinics, hospitals and pharmacies, it is essential for healthcare professionals to have a correct knowledge of the pathology – to immediately recognize its symptoms – and the measures to be taken to procure and administer Human Rabies Immunoglobulins based prophylaxis in combination with the rabies vaccine.

References:

The burden of rabies. Last reviewed September 25, 2017. Accessed March 4, 2019. https://www.cdc.gov/features/dsrabies/index.html