Pathophysiology of Myelofibrosis - Case Study Example

The Pathophysiology of Myelofibrosis Treatment and Case Study   Contents Purpose of this Paper This paper is about a case of a patient with myelofibrosis. It will cover three major elements: the Pathophysiology of myelofibrosis, the treatment of myelofibrosis, including their significance, and the relation of this discussion to the case of Mr. Spring, whose laboratory results have been given at two time periods. Pathophysiology of Myelofibrosis Myelofibrosis is a complicated syndrome, with over twenty synonyms and a variety of presentations (Lewis, 1985). Some of the names associated with the syndrome include Agnogenic Myeloid Metaplasia, and Myelofibrosis with Myeloid Metaplasia (Merck Manual, 2005). They are therefore heterogeneous diseases which occur within the bone marrow within the hematopoietic stem cell. These cells produce large numbers of cells which mature fairly normally, but later result in rapid destruction of mature blood cells in the circulating bloodstream, primarily in the spleen (Vainchenker, 2005) Myelofibrosis can be associated with malignant diseases, such as leukemias, polycythemia, Hodgkin’s lymphoma and cancer with marrow metastases. It is also associated with reactions to infections (TB, osteomyelitis) and toxins, including X- or Y-Radiation and benzene (Advani, 2008). Recent research results in molecular biology have pointed to some causes of myelofibrosis. An exciting discovery was the identification of the JAK2 V617F mutation in patients with myeloproliferative disorders (Villeval, 2006). It has been demonstrated that this factor is present in many patients with myeloproliferative disorders, including 90% of polycythemia vera (PV) and about 50% of thrombocythemia and idiopathic myelofibrosis patients. This finding of an underlying genetic mutation for many myelofibrotic patients suggests that future therapies may be developed which are more targeted to the basic underlying causes of the disease. The diagnosis of myelofibrosis starts with a peripheral blood film. Because myelofibrosis can result in a large number of circulating blood fragments, it is advisable to support automated hematology analyzers’ CBC results with a manual film. In most cases, myelofibrosis is diagnosed in the earlier stages with splenomegaly, or an enlarged spleen. It can cause an infarction of the spleen, anemia (which is most probably related to spleen function) or increases in LDH which are not linked with other causes. As the spleen is an important part of blood cell production and destruction, a blood cell morphological study can help to rule in or rule out myelofibrosis as the causative factor for splenomegaly. Patients with myelofibrosis live an average of five years after onset. The multiple and confusing signs of myelofibrosis can delay diagnosis, however. There are a number of methods used to treat myelofibrosis. These include androgen therapy, chemotherapy, and methods to reduce or eliminate the spleen’s effect on the disease, radiation or splenectomy. Treatment of Myelofibrosis through a Splenectomy The multiple presentations of myelofibrosis can lead to different treatment options. Those patients with essential thrombocythemia can live relatively normal lifespans, even if diagnosed relatively late in life, without removal of the spleen (Chim, 2005). Cin et al found that patients’ survival rates were 80% after 10 years from an average age of 65. Idiopathic myelofibrosis, on the other hand, can be associated with a shorter life expectancy, particularly for those patients who migrate from idiopathic myelofibrosis to acute leukemia (Xu, 2005). Myelofibrosis can be ameliorated closer to the source through bone marrow transplants, particularly for younger patients. As expressed by von Besien at the University of Chicago: Myelofibrosis is…characterized by progressive obliteration of the marrow space by fibrosis, extramedullary hematopoiesis, splenomegaly and presence of immature hematopoietic cells in the blood. (von Besien, 2003) One of the reasons that bone marrow transplantation was thought a poor option for patients in the past is that there was a concern about the high presence of fibrotic tissue in the bone marrow space. While this remains a concern, some clinical work with bone marrow transplants demonstrates that this is a viable option, despite space concerns in the bone marrow (Deeg, 2003). It is clear from clinical evidence, however, that the younger patients are at the time of transplant, the more likely that they will survive with near-normal life spans. In addition, patients who have high Dupriez scores (which include hemoglobin levels and white blood cell counts) tend to respond better to transplantation than those with lower scores. In any event, transplantation carries its own set of risks, from graft-versus-host disease (Rocha, 2000)to the risks of contracting diseases, from Eppstein-Barr (Gustafsson, 2000) to metastatic solid-tumor cancers. (Curtis, 1997). In addition, it may be difficult to find a suitable donor who is willing to endure the often-painful procedure to extract bone marrow. The success of bone marrow transplantation can depend on the degree of myelofibrosis before bone marrow transplantation. In some patients admitted for bone marrow transplantation, it was found that there was an over three-fold increase in fibrotic content as compared to normal fiber content in 26% of the patients. Post-transplant myelofibrosis recurred more frequently and more insidiously with patients who had high pre-transplant fibrotic tissue in their bone marrow. (Deeg, 2003) In general, the treatment of myelofibrosis with bone marrow transplantation has been limited to those patients where a longer-term survival rate is desirable, and where the prognosis for the disease is better. This tends to limit such transplants to patients who are otherwise fairly healthy, and who are under the age of 55. (Thiele, 2000) Splenectomy is associated with a shorter time to recurrence than bone marrow transplant, but a great deal of the success rate depends on the sources and symptoms of the disease. If a patient is suffering from agnogenic myeloid metaplasia, for example, it is likely that the spleen will recover some hemopoietic capabilities. There is still a relatively high mortality rate associated with splenectomy—about 10% of patients die during the operation. In addition, losing the function of the spleen can compromise other functions in the body, including assisting donor cells for stem cell transplants for follow-on treatment for myelofibrosis, and can compromise immune response (Li, 2001). In the future, as we learn more about hemopoietic stem cell transplants, it could be that these procedures replace some of the current splenectomy therapies, particularly for older patients who may not tolerate a splenectomy, or who may have concerns about the effect on immune response. Case of Mr. George Spring Mr. Spring is about 74 years old. He presents with a regular blood pressure and heartbeat, has a weight within normal range, and has good oxygen saturation and respiration. He is taking a number of drugs for his conditions. Some of these drugs may be related to his myelofibrosis, while others are for other conditions. These include: - Hyroxyurea 500mg TDS: this is a chemotherapeutic agent for solid and myeloid tumors - Aspro 320mg half daily: this is aspirin, which may increase bleeding. This could be a concern before surgery. - Centrum Select: this is a multi-vitamin. If there is Vitamin K present, it could increase clotting. - Maxlon 10mg daily: This is used to control vomiting, and may be related to the chemotherapy he is receiving. - Restaut 25 mg daily: No indication of this pharmaceutical - NurofenPlus: This is a pain medication which contains codeine and ibuprofen, which also helps to reduce swelling/inflammation - NBM from midnight: no bowel movement. - 4 units of packed red blood cells today: a clear indication of advanced red blood cell destruction. Day of surgery Moderate loss of blood: 6 units in operating theater. This is relatively moderate considering the blood loss generally encountered during a splenectomy (Shayuni, 1999). Results post-op: sats slightly lower, no fever, lowered blood pressure (which is to be expected post-splenectomy). Follow-up after three years Normal hemoglobin and MCV levels, normal pH Partial thromboplastin time short (should be 60-70 seconds). This could indicate a higher potential for clotting APTT within range (31) Normal INR Na: normal, Cl normal, K slightly elevated Creatinine level normal, Urea slightly low. This indicates that the protein intake is slightly below normal. The normal creatinine means that the kidneys are performing well. Conclusion from results after three years Mr. Spring has had a fairly normal recovery from his splenectomy. Although there are no platelet counts indicated here, Mr. Spring’s incipient myelofibrosis-caused anemia appears to have disappeared. One can expect that Mr. Spring’s energy level is higher, he is relatively free of pain, and that he has a fairly good prognosis. One should check for incipient signs of heart disease, as Mr. Spring’s higher PTT levels may indicate a higher risk of ischemic stroke or heart disease. He should maintain his daily aspirin for this. This relatively abbreviated patient history and follow-up information does not give enough indication of Mr. Spring’s general medical state upon admission for surgery. It also does not give enough follow-up information to indicate if Mr. Spring is suffering from co-morbidities. If one assumes that myelofibrosis was his primary and sole disease at the time of admission, one can conclude that the splenectomy was successful in reducing the symptoms of anemia and pain. It would be helpful to know if Mr. Spring’s physician considered a bone marrow transplant. His age at the time (about 70) was higher than the previous standard for bone marrow transplants, but advances in stem cell therapy and tissue typing may have made Mr. Spring’s prognosis better for such a procedure. It would also be helpful if the case showed Mr. Spring’s WBC count and the results of a blood smear (not just Hb and simple blood count information), including cell fragments. As we have seen from previous literature, the prognosis for such a patient is improved if the WBC count and blood smear results are near normal ranges. Bibliography Advani, A. a. (2008). Myloproliferative Disorders. Retrieved January 17, 2008, from Cleveland Clinic: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hematology/mdisorders/mdisorders.htm Chim, C.-S. K.-L. (2005). Long-term Outcome of 231 Patients With Essential Thrombocythemia. Archives of Internal Medicine , 2651-2658. Curtis, R. R. (1997). Solid Cancers after Bone Marrow Transplantation. NEJM , 897-904. Deeg, H. G.-P. (2003). Allogenic hematopoietic stem cell transplantation for myelofibrosis. Blood , 3912-3918. Gustafsson, A. L.-Z. (2000). Epstein-Barr virus (EBV) load in bone marrow transplant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells. Blood , 807-814. Lewis, S. (1985). Myelofibrosis: Pathophysiology and Clinical Management. Brussels: Marcel Dekker. Li, Z. a. (2001). Pros and cons of splenectomy in patients with myelofibrosis undergoing stem cell transplantation. Leukemia , 465-467. Merck Manual. (2005, November). Myelofibrosis. Retrieved January 17, 2008, from Merck: http://www.merck.com/mmpe/sec11/ch141/ch141c.html Rocha, V. W.-J. (2000). Graft-Versus-Host Disease in Children Who Have Received a Cord-Blood or Bone Marrow Transplant from an HLA-Identical Sibling. NEJM , 1846-1854. Shayuni, R. (1999). Invited Critique: Laparascopic Splenectomy. Arch Surg , 103. Thiele, J. K. (2000). Relevance and dynamics of myelofibrosis regarding hematopoietic reconstitution after allogeneic bone marrow transplantation in chronic myelogenous leukemia - a single center experience on 160 patients. Bone Marrow Transplantation , 275-281. Vainchenker, W. a. (2005). A Unique Activating Mutation in JAK2 (V617F) Is at the Origin of Polycythemia Vera and Allows a New Classification of Myeloproliferative Diseases. Hematology Am Soc Hematol Educ Program , 195-200. Villeval, J. J. (2006). New insights into the pathogenesis of JAK2 V617F-positive myeloproliferative disorders and consequences for the management of patients. Semin Thromb Hemost , 341-351. von Besien, K. (2003). Transplantation for myleofibrosis: yes! But for whom? Blood , 3857. Xu, M. B. (2005). The constitutive mobilization of bone marrow-repopulating cells into the peripheral blood in idiopathic myelofibrosis. Blood , 1699-1705. Read More