Disorders of Platelets and Focus on von Willebrand Disease

The hemostatic system consists of platelets, coagulation factors, and the endothelial cells lining the blood vessels. The platelets arise from the fragmentation of the cytoplasm megakaryocytes in the bone marrow and circulate in blood as disc-shaped anucleate particles. 

Under normal circumstances, the resistance of the endothelial cell lining to interactions with platelets and coagulation factors prevents thrombosis.

Platelets play a primary role in this process, interacting with subendothelium-bound von Willebrand factor (vWf) via the membrane glycoprotein (GP) Ib complex. This initial interaction (platelet adhesion) sets the stage for other adhesive reactions that allow the platelets to interact with each other to form an aggregate. 

he platelet GP IIb/IIIa complex mediates platelet-to-platelet interactions (platelet aggregation). On resting platelets, GP IIb/IIIa is unable to bind fibrinogen or vWf. Platelet activation allows binding of these proteins, which bridges adjacent platelets. Morphologically, the platelets change dramatically from discs to spiny spheres in a process called shape change.

Platelets contain 2 unique types of granules: the alpha granules and the dense granules. The alpha granules contain hemostatic proteins such as fibrinogen, vWf, and growth factors (eg, platelet-derived growth factor). The dense granules contain proaggregatory factors such as adenosine 5'-diphosphate (ADP), calcium, and 5-hydroxytryptamine (serotonin). During activation, the granules are centralized and their contents are discharged into the lumen of the open canalicular system, from which they are then released to the exterior 

when platelets are activated, negatively charged phospholipids move from the inner to the outer leaflet of the membrane bilayer. This negative surface provides binding sites for enzymes and cofactors of the coagulation system, resulting in the formation of a clot (secondary hemostasis).

Pathophysiology of Platelet Disorders

Platelet disorders lead to defects in primary hemostasis and produce signs and symptoms different from coagulation factor deficiencies (disorders of secondary hemostasis). The body's reaction to vessel wall injury is rapid adhesion of platelets to the subendothelium. The initial hemostatic plug, composed primarily of platelets, is stabilized further by a fibrin mesh generated in secondary hemostasis. The arrest of bleeding in a superficial wound, such as the bleeding time wound, almost exclusively results from the primary hemostatic plug.

Hence, primary hemostatic disorders are characterized by prolonged bleeding time, and the characteristic physical examination findings are petechiae and purpura. In comparison, defects in secondary hemostasis result in delayed deep bleeding (eg, into muscles and joints) and the characteristic physical examination finding is hemarthrosis. Hemarthrosis and muscle hematomas are not present in primary hemostatic disorders.

Disorders of Platelet Function

von Willebrand disease

von Willebrand disease (vWD) is the most common inherited bleeding disorder. It is autosomal dominant, and its prevalence is estimated to be as high as 1 case per 1000 population.

The hallmark of von Willebrand disease is defective platelet adhesion to subendothelial components caused by a deficiency of the plasma protein vWf. This factor is a large, multimeric protein that is synthesized, processed, and stored in the Weibel-Palade bodies of the endothelial cells, and secreted constitutively following stimulation.

vWf has a major role in primary hemostasis as mediator of the initial shear-stress–induced interaction of the platelet to the subendothelium via the GP Ib complex. In addition, von Willebrand protein acts as a carrier and stabilizer of coagulation factor VIII by forming a complex in the circulation.

In the absence of vWf, the factor VIII activity level is low. In classic hemophilia A, the factor VIII activity level is low because of a defect in factor VIII itself, whereas in von Willebrand disease, the factor VIII activity level is low because of a deficiency in its carrier protein.

von Willebrand disease is a relatively mild bleeding disorder, except in the occasional patient who is homozygous for the defect and who has severe bleeding often indistinguishable from classic hemophilia. The bleeding manifestations are predominantly skin-related and mucocutaneous (ie, easy bruising, epistaxis, GI hemorrhage).

Most bleeding episodes occur following trauma or surgery. In women, menorrhagia is common, often exacerbated by the concurrent administration of nonsteroidal anti-inflammatory drugs. Pregnant patients with this disease usually do not have problems.

Bleeding time is prolonged in persons with von Willebrand disease. Because the von Willebrand protein is phase-reactant (ie, increased synthesis in the presence of inflammation, infection, tissue injury, and pregnancy), a mild prolonged bleeding time may be normalized, resulting in difficulty in diagnosis.

In addition to the prolonged bleeding time, characteristic abnormalities in platelet aggregation tests occur. In patients with von Willebrand disease, platelets aggregate normally to all agonists except the antibiotic ristocetin, which induces binding of the von Willebrand protein to platelets, similar to what happens with platelets following vessel wall injury in vivo. Ristocetin-induced platelet aggregation correlates with the platelet-aggregating activity of the von Willebrand protein. levels of coagulation factor VIII are also low, resulting from a decrease in vWf.

Variants of von Willebrand disease

Although the common form of von Willebrand disease (type I) results from a quantitative deficiency of vWf, the variants result from abnormalities in the von Willebrand protein.

A common variant (type IIA) of von Willebrand disease results from functionally defective vWf that is unable to form multimers or be more susceptible to cleavage by ADAMTS13. Larger multimers are more active in mediating platelet vessel-wall interaction. In these variants, the factor VIII level may be normal.

In the type IIB variant, the von Willebrand protein has heightened interaction with platelets, even in the absence of stimulation. Platelets internalize these multimers, leading to a deficiency of von Willebrand protein in the plasma.

A disorder of platelet GP Ib has also been described. In this condition, increased affinity for von Willebrand protein in the resting stage leads to the deletion of plasma von Willebrand protein. This disease is called pseudo von Willebrand disease or platelet-type von Willebrand disease.

Type III von Willebrand disease is a severe form of von Willebrand disease that is characterized by very low levels of vWf and clinical features similar to hemophilia A, but with autosomal recessive inheritance. This condition results from a homozygous state or double heterozygosity.

Bernard-Soulier syndrome

Bernard-Soulier syndrome results from a deficiency of platelet glycoprotein protein Ib, which mediates the initial interaction of platelets with the subendothelial components via the von Willebrand protein. It is a rare but severe bleeding disorder. Platelets do not aggregate to ristocetin. The platelet count is low, but, characteristically, the platelets are large, often the size of red blood cells, and may be missed on complete blood counts because most automatic counters do not count them as platelets.

Glanzmann thrombasthenia

Glanzmann thrombasthenia results from a deficiency of the GP IIb/IIIa complex. Platelets do not aggregate to any agents except ristocetin. The more severe type I results from a complete absence of the GP IIb/IIIa complex, whereas in the milder type II, some of the GP IIb/IIIa complex is retained.

Both Bernard-Soulier syndrome and Glanzmann thrombasthenia are characterized by lifelong bleeding. Although platelet transfusions are effective, they should be used only for severe bleeding and emergencies, because alloantibodies often develop in these patients.

Etiology of Platelet Disorders

Platelet disorders can involve either a decreased number of platelets (thrombocytopenia) or defective platelet function. Functional disorders of platelets can be inherited (rare) or acquired (common). Platelet aggregation tests are useful in differentiating various disorders of platelet function. In all cases of thrombocytopenia, the peripheral blood smear must be reviewed to confirm the thrombocytopenia. This review is crucial.

Spurious thrombocytopenia can occur due to aggregates forming in the specimen. In addition, dilutional thrombocytopenia may occur in situations of fluid replacement or blood component replacement without platelet support.

Thrombocytopenia can be further divided into increased destruction or decreased production. Thrombocytopenia resulting from increased destruction occurs either by an immune mechanism or increased consumption.

Platelets are consumed intravascularly by the activation of the coagulation process (diffuse/disseminated intravascular coagulation [DIC]) or by deposition on damaged endothelial cells (microangiopathy). Production defects result from those diseases that cause bone marrow failure, such as aplastic anemia, infiltration by leukemia or another malignancy, fibrosis or granulomatous disorders, or tuberculosis.

Causes of thrombocytopenia related to increased destruction include 

(1) Immune thrombocytopenias (eg, autoimmune, alloimmune, drug-induced) and 

(2) Increased consumption (eg, DIC, TTP). Causes of thrombocytopenia related to decreased production include bone marrow depression.

Disorders of platelet function are as follows:

• Disorders of platelet adhesion (von Willebrand disease, Bernard-Soulier syndrome)
• Disorders of aggregation (Glanzmann thrombasthenia)
• Disorders of secretion
• Disorders of thromboxane synthesis
• Acquired disorders of platelet function (drugs [eg, aspirin, NSAIDs, alcohol])
• Uremia
• Paraproteins
• Fibrin degradation products
• Myelodysplasia or a myeloproliferative syndrome

Treatment of von Willebrand Disease

Desmopressin (DDAVP) is a vasopressin analogue that releases vWf from endothelial cells.

Most patients with type I von Willebrand disease can be treated with DDAVP for minor surgeries and dental procedures. The usual dose is 0.3 μg/kg infused slowly approximately 30 minutes before an operative procedure. This dose can be repeated once a day for 2-3 days, after which it is ineffective because of tachyphylaxis. Other adverse effects occasionally include a hypertensive response and hyponatremia.

An intranasal preparation of DDAVP has been made available for individuals with von Willebrand disease and is administered at a dose of 150 μg or 300 μg (ie, 150 μg per nostril). The more diluted preparation is used in patients with diabetes insipidus and does not increase vWf levels.

DDAVP does not usually increase factor VIII levels in patients with type IIA and can induce thrombocytopenia in patients with type IIB or pseudo von Willebrand disease.

Replacement therapy is used for more extensive surgeries or trauma and for patients with type II and type III disease. The treatment of choice is vWf concentrates (Humate-P or Alphanate). These preparations are heat-treated, and the solvent is extracted; therefore, they are considered safe from viral contamination.

The dose is calculated based on ristocetin cofactor units (usual dose is 50-100 U/kg). The factor VIII level often rises following the infusion of von Willebrand protein concentrate, and it remains elevated for at least for 40 hours, reflecting the half-life of von Willebrand protein rather than that of factor VIII. The need for further doses is often assessed based on clinical criteria rather than blood test results.

Cryoprecipitate has approximately 100 U of factor VIII per bag and has all multimeric forms of vWf. Despite screening tests, patients have a small risk developing viral infections.

Highly purified preparations of factor VIII or recombinant factor VIII should not be administered to patients with von Willebrand disease, because these preparations have very little von Willebrand protein.

Source: Scopus

by

AKSHAYA SRIKANTH

Pharm.D Resident

Hyderabad, India

Digesting It All!

The digestive system, or gastrointestinal (GI) tract, is a very complex machine requiring many different organs to work together in concert. The ultimate job of the GI tract is to absorb or admit the nutrients necessary to keep the body healthy, while at the same time rejecting or dispelling those substances that are toxic. To accomplish this important job, the membrane that lines the entire GI tract acts as a selective barrier—essentially taking in what is “good” and rejecting that which is “bad.”

There are three key steps to the digestive process: absorption, assimilation and elimination. Absorption begins the moment food crosses from the outside world into the long intestinal tube that makes up the GI tract. As food makes its way through the intestines, absorption continues across the intestinal wall and into the bloodstream. Assimilation is the step whereby nutrients actually enter the cells of the body; and finally,elimination may be thought of as the clean-up process, whereby the body gets rid of the waste products.

Not surprisingly, these critical steps require an incredible amount of energy to get the job done. A very large blood supply is also necessary and, in fact, the GI tract has the largest blood supply of any system in the body. It uses one-third of the overall blood flow from the heart to carry out its continual work.

Normal Flora of the GI Tract

What are the factors involved in healthy digestion? One key component is the internal “ecosystem” of the digestive tract. This self-contained environment within the walls of the stomach, colon and intestine is the home of more than 400 species of bacteria—most of them beneficial and protective in their roles. These normal or “friendly” flora of the GI tract number in the trillions, the majority of which reside in the colon. In fact, healthy adults typically have five to eight pounds of living bacteria in their GI tract.

The reason we have so much bacteria happily living in our digestive system is that they produce nutrients essential to digestion. These bacteria actually nourish the cells of the GI tract by producing essential short-chain fatty acids. Moreover, a number of other important nutrients are produced only through the bacterial fermentation of our food. Without the nutrients from this friendly flora, the lining of the GI tract would not function properly.

Another normal and healthy component of the digestive system is a strain of yeast called candida albicans, or candida for short. Candida is ubiquitous, covering virtually every living thing on this planet. Under healthy conditions it does not cause health problems, but when the delicate balance that normally exists inside the body is tipped, candida can grow out of control and create a wide array of mild to severe health disorders. This then becomes a candida infection, or candidiasis.

Tipping the Balance

If dangerous bacteria, parasites, or an overgrowth of candida replace the friendly bacteria that line the GI tract, a process of inflammation can begin. This process may even affect other cells and organs of the body that are susceptible to inflammation.

According to Dr. Joseph McWherter in Avoiding Breast Cancer, candida produces estrogen-like compounds that can disrupt normal hormonal function. For example, an over-growth of candida can lead to excessive estrogen production. When candida grows out of control, it can also release part of its fungal wall, which induces inflammation. Such chronic inflammatory changes may eventually disrupt the surrounding environment of the breast cell. Adverse changes to the normal intestinal bacterial flora, such as that caused by long-term use of antibiotics, can double the risk of breast cancer.

An overgrowth of yeast in the intestines can lead to a wide variety of chronic digestive problems, such as bloating, diarrhea, chronic stomach inflammation, and heartburn. It can also cause symptoms that include fatigue, headaches, muscle aches, and chronic flu-like symptoms. Beyond these digestive and systemic discomforts, candidiasis is also often associated with female disorders like chronic vaginal discharge, chronic vaginal yeast infections, chronic urinary canal inflammation, vaginitis, premenstrual syndrome, endometriosis, painful breasts, and other hormonal imbalances.

Common Symptoms of GI Disorders

The symptoms of many of the major digestive system disorders are not specific to just one disease or condition. Abdominal pain, diarrhea, gas, bloating, and constipation can accompany any of the GI health issues, so it may be helpful to review these uncomfortable symptoms.

Abdominal pain can vary in its location, frequency and intensity with any kind of GI disorder. What is important to know is that certain kinds of abdominal pain, such as that described for pancreatitis, may signal a serious problem.

Diarrhea is the frequent passage of watery stools and is most often caused by intestinal irritation, incomplete digestion of food, use of certain drugs, food poisoning or food allergies.

Gas and/or bloating occur when there is excessive gas in the stomach and intestines (also called flatulence) and can be a sign of incomplete digestion. Three major sources of gas in the GI tract are gas swallowed from the air, gas formed by a chemical reaction of hydrochloric acid from the stomach and pancreatic secretions, and gases formed through bacterial fermentation in the colon. Those who are lactose intolerant or overly sensitive to foods such as legumes and cruciferous vegetables may experience increased gas production.

Constipation refers to infrequent or incomplete bowel movements, often characterized by stools that are hard and difficult to pass due to slow transit time through the GI tract. Usually this is caused by insufficient dietary fiber, excessive dietary fat and or refined foods, side-effects of some medications, lack of exercise, dehydration or hormonal changes.

Digestive Diseases or Conditions

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a catch-all term for a multitude of symptoms and conditions that may involve any part of the GI tract, including the esophagus, stomach, small intestine, gallbladder, colon and bowel. Other commonly used terms that fall into this category include colitis, spastic colon or spastic colitis.

With IBS, the normally rhythmic muscular contractions of the GI tract become uncoordinated and irregular, which interferes with the normal movement of food and waste, often leading to accumulation and potentially a partial obstruction. Symptoms are similar to those of many GI disorders: pain, diarrhea, loss of appetite, nausea and vomiting.

Inflammatory Bowel Disease (Crohn’s Disease and Ulcerative Colitis)

Inflammatory bowel disease (IBD) is another catch-all term for chronic inflammation in the intestines. Crohn’s Disease and Ulcerative Colitis are two forms of IBD, both of which are potentially serious and can lead to malnutrition. In Crohn’s Disease, ulcerations occur along the small or large intestines, and the bowel wall thickens causing the GI tract to narrow, with all layers of affected tissue going through cycles of inflammation, damage and healing. The most common symptom is diarrhea. Ulcerative Colitis is a chronic inflammation of the large intestine. Symptoms include abdominal pain, diarrhea and rectal bleeding. Both diseases can cycle through periods of remission and flare-ups

Celiac Disease

In those with a genetic predisposition, this inflammatory disorder of the small intestine is triggered by exposure to gluten (wheat protein). This condition results in a malabsorption of nutrients; those affected may develop anemia due to a lack of iron, folate, and/or vitamin B12; or osteoporosis due to inadequate absorption of calcium and vitamin D. Celiac disease can lead to fertility problems in women if left untreated. Gas, abdominal cramping, weight loss, canker sores, fatigue and anemia all suggest difficulty digesting gluten and are common symptoms.

Gallbladder Disease

Gallbladder problems typically stem from inflammation, swollen ducts that restrict bile flow,or gallstones that block bile flow. A sedentary lifestyle, being overweight, and skipping meals are common factors in those with gallbladder problems. Food allergies can also trigger inflammation. Symptoms include indigestion, chronic gas, bloating, fatigue, and anxiety in chronic cases; and severe pain, nausea, and vomiting in an acute gallbladder attack.

Gastritis

Gastritis is an inflammation of the lining of the stomach that involves erosion of the upper-most mucosal layer. While many types of gastritis cause no symptoms, those that do can result in heartburn, pain in the upper abdomen, nausea, and vomiting.

Gastroesophageal Reflux Disease (GERD)

Often referred to as heartburn, this condition occurs when partially digested food from the stomach, along with hydrochloric acid (HCl) and enzymes, backs up into the esophagus (a process also known as reflux).The acidity of HCl can cause damage when it comes into contact with the delicate lining of the esophagus. Reflux (or regurgitation), chest pain, and difficulty swallowing are some of the most common symptoms of GERD.

GI Tract Infections

Although parasites, bacteria, viruses, fungi, worms and protozoa are ubiquitous, some can wreak havoc when infecting the GI tract. Some organisms can provoke hormone changes by binding estrogen, thus making it unavailable, while others can actually produce hormones leading to excess levels. Infections can cause a wide range of symptoms including diarrhea, cramps, gas and fatigue.

Leaky Gut Syndrome

The leaking of the gut wall through the gut lining can be triggered by a number of factors including food allergies, alcoholism, radiation, chemotherapy, infections and severe trauma. This compromises the barrier function of the digestive tract so that toxins and bacteria can seep into the bloodstream and be passed along to the liver. While common symptoms include vitamin deficiencies, gas, cramping, fatigue and poor concentration, development of an autoimmune disease, including allergies, may also be a sign of leaky gut syndrome.

Pancreatitis

Inflammation of the pancreas usually results from the blockage of the ducts of the pancreas, and can be caused by alcohol abuse, viral infection, or when gallstones become trapped in the ducts. The most classic symptom of acute pancreatitis is pain above the navel that spreads across the abdomen and to the back. Other symptoms may include nausea, vomiting, fever and weakness.

Ulcers

Ulcers are sores or lesions that develop in the mucus lining of the stomach. Once believed that stress was the major cause of peptic ulcers, most are associated with the presence of a bacterium called Helicobacter pylori between the lining of the stomach and the protective mucous layer. Common symptoms include severe pain (often worse between meals and at night) and black, tarry stools, which indicate internal bleeding.

Hormones and the GI Tract

While we typically associate the GI tract with all things digestive, it is important to know that the intestines are also the primary immune organs of the body, and the GI tract plays a major role in the body’s immune system. The digestive tract, along with the throat and mouth, provide an important defense against infection by potential pathogens—including bacteria, viruses, parasites, fungi and invasive forms of yeast.

The key to this defense is the presence of protective antibodies found in the saliva in the mouth, and the mucus throughout the entire digestive system. These anti-bodies are called secretory IgA (sIgA), and they function as the first line of immune defense as they block the invasion of unhealthy organisms. sIgA levels, which are often reported on saliva tests for DHEA and cortisol, diminish with chronic decreases in the adrenal hormones.

Adrenal Hormones

According to a 2012 study, both DHEA and cortisol levels “may be involved in exacerbating abdominal symptoms in individuals with IBS.” Study participants, some of whom were previously diagnosed with IBS, were exposed to stressful conditions and tested for hormone levels before, during and after the stressful event. The subjects with IBS had lower circulating DHEA levels and a higher ratio of cortisol to DHEA than subjects without IBS.

These results are not surprising because the adrenal hormones are key players in the immune system. DHEA, in particular, can affect healing from a GI tract disorder. In the case of intestinal tract allergies or invasion by pathogens, major inflammation may occur. DHEA, which promotes cell growth and repair, can help speed up repair of the inflamed mucosal tissues in the GI tract.

Cortisol, while typically associated with stress, also plays a role in the repair and healing of GI tract disorders. Cortisone, a synthesized form of cortisol, acts as an anti-inflammatory and anti-viral agent and is often prescribed for people suffering from IBS.

Female Hormones

The hormones we think of as female hormones (primarily estrogen and progesterone) also have significant effects on the health of the GI tract. The imbalances of these hormones can influence the movement of food through the intestines—some by speeding the process up, causing diarrhea, nausea and abdominal pain; and others by slowing things down and causing bloating and constipation.

It is quite common for post-menopausal women to be constipated. One study set out to test the effects of the female sex hormones progesterone and estradiol on the bowel movements of healthy postmenopausal women. The results showed that supplemental progesterone actually decreased the time it took for the colon to empty. The combination of progesterone and estradiol also produced looser stools and relief from constipation.

Women often notice changes and experience other GI tract discomforts (diarrhea and bloating, for example) throughout their menstrual cycle. These symptoms are most common during the luteal phase or second half of the cycle. The increased production of progesterone and estrogen during a woman’s menstrual cycle may have a direct effect on the digestive system. Such hormonal fluctuations may cause changes in the natural ecosystem of the GI tract and indirectly lead to GI tract discomfort. In The Yeast Syndrome, Dr. John Trowbridge, notes that candida growth flares with increases of progesterone.

The gallbladder stores bile, which is released when we eat fatty foods, in order to aid in the digestion and absorption of fats. When hormone balance is disturbed so that it favors estrogen excess, or supplemental estrogens are taken in the form of Premarin® or birth control pills, bile tends to thicken and may ultimately lead to the development of gallstones.

The digestive system plays an important role in the proper disposal of estrogen from the body. When the bowel does not function properly, estrogen that is meant to be excreted by the intestines is sometimes recycled and reabsorbed into the bloodstream.

Excess activity of a specialized enzyme called beta-glucuronidase, which is involved in the reactivation of estrogen and prevents it from leaving the body, may also be responsible for the recycling and build-up of estrogen levels. The excess activity of beta-glucuronidase is triggered by an imbalance of the normal ecosystem of the GI tract.

Natural progesterone can be beneficial with regard to the gut’s healing process, according to Dr. Paul Lynn in the book Optimal Digestive Health. He frequently recommends progesterone for women with digestive disorders, and as a hormone with both anti-inflammatory and anti-stress properties, it has been shown to work as a natural relaxant in the GI tract.

Other Hormones at Work in the Gut

Thyroid hormone levels can also affect the proper functioning of the digestive system. In cases of hypothyroidism (when thyroid levels are too low), digestion in the stomach and intestines slows down, and the concentration of stomach acid and digestive enzymes may be diminished. Chronic constipation is a recognized symptom of hypothyroidism.

Finally, melatonin (a hormone produced primarily in the brain) also seems to alleviate the painful and bothersome symptoms of IBS. While melatonin from the brain is critical to sleeping and waking cycles, some melatonin is also produced in the stomach when we eat. This form of melatonin regulates the production of stomach acid and the enzyme pepsin, as well as the movement of food from the stomach. In one study, patients who took melatonin daily showed decreased gastrointestinal pain and rectal pain, and an improvement in the frequency of bowel movements.

My Conclusion

Given the many organs that comprise the digestive system and its complex internal environment—home to hundreds of species of normally friendly bacteria—it should come as little surprise that the GI tract is susceptible to a wide range of disorders.

To keep the GI tract functioning properly, there are many factors to consider. From the foods we eat, to the general ways in which we practice good health (such as adequate sleep and exercise), these factors can all influence the digestive system. And, as discussed here, hormone levels are another important factor.

While not intended to be comprehensive, we have introduced you to some of the roles that estrogens, progesterone, DHEA, cortisol, thyroid and melatonin hormones play in the absorption, assimilation and elimination functions of the GI system. It is important to consider the role of hormone balance and “digest” all that is presently known when it comes to keeping your digestive system as healthy as possible.

by

Akshaya Srikanth

Pharm.D Resident

Hyderabad, India

Risk for Fatal Adverse Events Linked With Certain Cancer Drugs

Vascular endothelial growth factor (VEGF) is an important mechanism for the growth of solid tumors, and inhibition of VEGF receptors has emerged as a major pathway to treat cancer. The authors of the current study perform a review of tumors approved for treatment by the US Food and Drug Administration with sorafenib, sunitinib, or pazopanib. These tumors include renal cell cancer, hepatocellular carcinoma, and gastrointestinal stromal tumor.

A previous meta-analysis of the anti-VEGF monoclonal antibody bevacizumab demonstrated that this therapy was associated with a 33% increase in the risk for fatal adverse events vs traditional chemotherapy alone. The current meta-analysis by Choueiri and colleagues queries the risk for fatal adverse events associated with VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) from clinical trials of patients with cancer.
STUDY SYNOPSIS AND PERSPECTIVE
The risk for fatal adverse events associated with several targeted cancer drugs have come from a large meta-analysis of clinical trials, which was published on February 6 in

the 

Journal of Clinical Oncology

The drugs investigated were pazopanib (Votrient, GlaxoSmithKline), which is approved for use in renal cell carcinoma; sorafenib (Nexavar, Bayer & Onyx), which is approved for use in renal cell carcinoma and hepatocellular cancer; and sunitinib (Sutent, Pfizer), which is approved for use in renal cell carcinoma and gastrointestinal stromal tumors. All 3 products are VEGFR TKIs.

The meta-analysis, which examined data on 4679 patients from 10 clinical trials, found that these 3 drugs were associated with fatal adverse events at a rate that was about twice that seen in the placebo groups. The crude incidence of fatal adverse events was 1.5% in patients taking these drugs, compared with 0.7% in patients in the placebo or control groups (relative risk [RR], 2.23; P = .023).

The most common cause of death was hemorrhage; the second most common was myocardial ischemia. Liver failure and congestive heart failure were also reported.

Senior author Toni Choueiri, MD, from the Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, said that clinicians need to be aware of the risks associated with these drugs.

"There is no doubt that for the average patient, these drugs have benefits," Dr. Choueiri said in a statement. In fact, these drugs represent a major step forward in the treatment of several malignancies, and they have led to significant improvements in patient outcomes.

However, they are associated with a significant increase in the risk of developing fatal drug-related events, and "practitioners must be aware of the risks associated with their use and must provide rigorous monitoring to continue to improve patient outcomes," the researchers note.

"While the absolute incidence of these fatal side effects is very small, the relative risks are higher," Dr. Choueiri noted. In addition, the patients in this meta-analysis were participating in clinical trials and all had adequate organ function at study entry, so the overall incidence and risk for unreported fatal adverse events could be higher in common medical practice.

Similar Data on Bevacizumab

An increase in the risk for fatal adverse events has also been reported for bevacizumab (Avastin, Genentech/Roche), which inhibits VEGF but by another mechanism; it is a monoclonal antibody that binds to VEGF. The data on bevacizumab, reported last year, came from a meta-analysis of clinical trials involving 10,217 patients, which found a significantly higher rate of fatal adverse events associated with bevacizumab than with chemotherapy alone (2.5% vs 1.7%; RR, 1.46; P = .01).

This increased risk and incidence of fatal adverse events reported for bevacizumab "are on the same scale" as those described in this meta-analysis looking at pazopanib, sorafenib, and sunitinib, note Dr. Choueiri and colleagues. In both cases, hemorrhage was the cause of death in the majority of patients.

When the bevacizumab data were published (JAMA. 2011;305;487-494), an accompanying editorial questioned the overall benefit of adding bevacizumab to chemotherapy (JAMA. 2011;305:506-508). Editorialist Daniel Hayes, MD, from the University of Michigan Comprehensive Cancer Center in Ann Arbor, speculated that the increased rate of fatal adverse events "might negate any survival benefit."

Medscape Medical News asked Dr. Hayes to comment on the findings of an increased rate of fatal adverse events with pazopanib, sorafenib, and sunitinib.

"I really don't have much to add. The data are as they are," he said. "All drugs have benefits and risks, and it is up to caregivers, patients, and society to decide if the benefits outweigh the risks."

"It seems like we sometimes throw out one or the other side of this equation when reviewing therapeutic strategies," Dr. Hayes explained. "Regardless, certainly one cannot determine the benefit/risk ratio if we don't have a legitimate estimate of the latter, so this is an important paper."

Breakdown of the New Findings

Of the 4679 patients in this meta-analysis, 2856 were involved in sorafenib clinical trials, 1388 were involved in sunitinib trials, and 435 were involved in pazopanib trials.

Although there were more fatal adverse events reported for sorafenib than for the other 2 drugs, there was no statistically significant difference in the RR for the 3 drugs, the researchers note. All 3 products have a similar mechanism of action (antagonizing the intracellular domain of VEGF and blocking downstream signaling), and all 3 drugs have similar class-effect toxicity profiles, they add.

Half of the 19 study deaths (47.5%) that occurred in patients taking pazopanib, sorafenib, or sunitinib were due to hemorrhage. The majority of these deaths from hemorrhage (79%) occurred in patients with non–small-cell lung cancer (NSCLC). This is not surprising, the researchers note, because NSCLC lesions are known to be highly necrotic and have a propensity to bleed, even without the inhibition of the VEGF pathway.

The second most common reason for death was myocardial ischemia (n = 6), the researchers note. Other causes were abnormal hepatic function or failure (n = 40), sepsis (n = 3), congestive heart failure (n = 2), ischemic stroke (n = 1), pulmonary embolism (n = 1), dehydration (n = 1), and sudden death (n = 1).

The findings of myocardial infarction and other cardiovascular events is consistent with previous analyses, the researchers note. Dr. Choueiri and colleagues have previously reported a significant increase in the risk for arterial thromboembolic events and in the risk for bleeding associated with sorafenib and sunitinib. They have also reported an increase in the risk for congestive heart failure with bevacizumab.
STUDY HIGHLIGHTS

• The main study outcome was the relationship between treatment with VEGFR TKIs and incident fatal adverse events. Researchers compared results from trials that included a placebo vs an active treatment group, and they also examined the quality of included research.
• Of 15 studies carefully reviewed for eligibility, 10 trials with a total of 4679 participants were included in the current meta-analysis. 6 of these studies focused on sorafenib, and 3 examined sunitinib. Only 1 study tested pazopanib.
• In general, patients eligible for participation in the included research were free of other serious illness. Types of tumors included in the research were renal cell cancer, hepatocellular carcinoma, melanoma, NSCLC, breast cancer, and pancreatic neuroendocrine tumor.
• Most studies were placebo controlled, and nearly all were double blinded. Overall, study quality was found to be very good, and there was no evidence of publication bias.
• The rate of fatal adverse events ascribed to treatment with VEGFR TKIs was 1.5%. There was no significant difference between individual VEGFR TKIs in promoting fatal adverse events.
• Hemorrhage was the most common cause of death in cases of fatal adverse events, accounting for 47.5% of all deaths in the meta-analysis. Myocardial infarction was the next most common cause of fatal adverse events, but it represented only 15% of all deaths.
• The overall risk for fatal adverse events associated with treatment with VEGFR TKIs was 2.23 (95% confidence interval, 1.12 - 4.44). Again, the relative risk for fatal adverse events in comparing the 3 individual VEGFR TKIs was similar.
• There was also no difference in comparing the risk for fatal adverse events associated with treatment with VEGFR TKIs among patients with renal cell cancer or other types of cancer.
• VEGFR TKIs were associated with higher risks of fatal adverse events in placebo-controlled trials as well as in studies with an active comparator treatment.

My Conclusion:

The current study by Choueiri and colleagues suggests that the VEGFR TKI inhibitors sorafenib, sunitinib, and pazopanib can promote a higher rate of fatal adverse events among patients with cancer. This risk was similar in comparing individual VEGFR TKIs, and hemorrhage was the leading cause of death.

Source: JCO

by

Akshaya Srikanth

Pharm.D*

Hyderabad, India

Targeted cancer therapy

The phrase 'the war against cancer' might have become clichéd over the decades, but it does help to portray how much we have relied on advances in weaponry to score numerous victories against the disease. Tamoxifen proved that cancer treatments can behave like 'magic bullets' (see Milestone 5) and avoid the toxic effects of traditional chemotherapy treatments. Yet, the discovery of oncogenes offered the possibility of creating 'laser-guided' treatments — drugs that strike at the heart of tumours by zeroing in on the genetic abnormalities that make cells grow uncontrollably.

The first of these molecular-targeted treatments was a monoclonal antibody called trastuzumab (Herceptin; Genentech). Trastuzumab blocks the human epidermal growth factor receptor 2 (HER2) protein that is overexpressed by gene amplification in around 25% of breast cancer cases. Patients with this form of breast cancer have a worse prognosis; however, in the first trial carried out with trastuzumab, Dennis Slamon and colleagues found that women with advanced breast cancer who received the new drug as well as the usual chemotherapy fared better than those who received chemotherapy alone.

If trastuzumab proved that molecular-targeted treatments could effectively treat cancer, then a drug for chronic myeloid leukaemia (CML) called imatinib mesylate (Glivec; Novartis) changed our thinking about the power of designing such therapies. CML is a rare cancer that is characterized by the union of chromosomes 9 and 22, which fuses two genes called breakpoint cluster region (BCR) and Abelson murine leukaemia viral oncogene homologue 1 (ABL; also known as ABL1), to form a tyrosine kinase that signals myeloid cells to grow and proliferate continuously (see Milestone 10). Imatinib mesylate was rationally designed to block the BCR–ABL active site, and when Brian Druker and colleagues carried out the first trial with the drug they found that almost all patients (98%) with therapy-resistant CML saw their blood counts return to normal. Yet, it turns out that imatinib mesylate is not as selective as first thought, and this promiscuity could help to treat other cancers. George Demetri and colleagues were the first to show that imatinib mesylate could treat patients with advanced gastrointestinal stromal tumours by blocking c-KIT.

Designing targeted drugs for more common and complex cancers, however, presents added challenges, as illustrated by the story of gefitinib (Iressa; AstraZeneca). Gefitinib blocks the activity of a tyrosine kinase called epidermal growth factor receptor (EGFR) that is overexpressed in 40–80% of lung cancers. Yet, gefitinib turns out to be effective in only 10–19% of lung cancer patients. Thomas Lynch, Daniel Haber and colleagues explained how the target protein governs whether the drug will work. Patients who respond to gefitinib have specific mutations clustered around the ATP-binding pocket of the EGFR protein where the drug binds, whereas patients who do not respond tend not to carry these mutations.

Equally important as knowing who will respond to treatments is knowing who will develop resistance, and Charles Sawyers and colleagues showed that this is also determined by the target protein. Six out of the nine patients studied, who had relapsed after imatinib mesylate treatment, acquired the same amino-acid substitution in the ABL kinase domain, which affects the interaction of the drug with the kinase; the other three showed BCR–ABL gene amplification.

Understanding the molecular underpinnings of response and resistance to these, and other molecular-targeted treatments, is helping to create a new wave of drugs that can harness or circumvent these mechanisms — some of which are already beginning to enter the clinic. The war against cancer might be far from being won, but the era of molecular-targeted treatments could prove to be one of the most important turning points in determining the outcome.

Source: Nature Medicine Milestones

by

Akshaya Srikanth

Pharm.D Internee

Hyderabad, India