Hematology Week 7 Summary

Question 31

Warfarin is metabolized through the liver and has the potential for numerous medication side effects. Which medications inhibit and induce warfarin metabolism?

• P450 Inhibitors
  • “IQ SMACKD”
    • IHN
    • Quinolones
    • Spironolactone
    • Macrolide
    • Amiodarone
    • Cimetidine
    • Ketoconazole
    • Dapsone
• P450 Inducers
  • “CRABS I”
    • Carbamazepine
    • Rifampin
    • Alcohol
    • Barbiturates
    • Sulfas
    • Imuran

Question 32

A 51 year old male is found to have splenomegaly on physical examination. His blood work shows a haemoglobin of 110g/L, white blood cell count of 122 with a left shift and platelet count of 900,000. He is immediately referred to a haematologist, who suspects chronic myelogenous leukemia.

What is the abnormality in CML and what therapies exist to treat it?

Points for discussion:

• CML is a myeloproliferative neoplasm due to the deregulated activation of the BCR-ABL tyrosine kinase resulting from the c-ABL oncogene from chromosome 9 justaposed to the BCR gene on chromosome 22. This is known as the t(9;22) translocation resulting in persistent granulocytic cell proliferation. A bone marrow biopsy is required to ensure there is no progression to accelerative or blast phase CML.
• A landmark trial by O’Brien et al published in 2003 comparing Imatinib to INF + Cytarabine confirmed a complete cytogenetic response in 69% of patients by 12 months of use.
• Imatinib binds to the site of tyrosine kinase activity, thereby preventing its ability to be phophorylated. Second line TKIs have recently been approved for use in first line CP-CML, and include Dasatinib and Nilotinib with the advantage of faster achievement of cytogenetic and molecular response times. Despite this, there is no evidence that there newer agents in fact improve overall survival.

O’Brien et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. New England Journal of Medicine 2003 March 13, 348 (11): 994-1004

Question 33

A previously healthy 25 year old patient presents with the following bloodwork following diagnosis of Burkitt’s lymphoma:

What is the major complication with his blood work and how should this be managed?

Tumor Lysis Syndrome: Caused by “dumping” of intracellular metabolites into the circulation.

Hallmarks:

• Hyperkalemia
• Hypocalcemia
• Hyperphosphatemia
• Hyperuricemia
• Renal failure

Most frequent in tumors with:

• High growth fractions
• Exquisite chemosensitivity

Examples: Lymphomas (esp. high grade), Leukemia, rarely in solid tumors

General treatment of tumor lysis syndrome:

• Aggressive IV fluid hydration, monitor u/o
• Allopurinol (300-600 mg/day)
• Rasburicase in case of contraindication for allopurinol
• Aggressive management of hyperkalemia
• Early dialysis and inotropic support as needed

Question 34

A 34 year old male is followed regularly for severe Hemophilia A. Points of discussion:

1. What is hemophilia A and what are its grades of severity?
2. Do the grades of severity correlate with the clinical phenotype?
3. What is the standard of care for a patient with severe Hemophilia A?

Points of Discussion:

• Hemophilia A is caused by a hereditary, X-linked, deficiency in coagulation factor VIII. The prevalence is approximately 1/5000 males born. Hemophilia A exhibit 3 levels of severity:
  • severe (FVIII activity levels <1%),
  • moderate (1-4.9%),
  • mild (>5%).
• In general, the risk for bleeding is linked to the degree of severity. In severe cases, initial hemorrhaging occurs before the age of 1 year, and in moderate cases bleeding more commonly starts later, i.e. at 1 to 2 years of age. Bleeding is spontaneous or occurs after minimal trauma. In mild hemophilia, bleeding problems are often related to surgery and injuries. Therefore, mild hemophilia might be diagnosed late in life, in connection with surgery.
• Modern hemophilia care should be centralized at bleeding disorders centers. These centers have treatment teams consisting of physicians (hematologists, rheumatologists, orthopedic surgeons), nurses, physiotherapists and social workers trained in bleeding disorders’ care. Primary prophylaxis with replacement of the missing FVIII coagulation factor was started in Sweden in 1958 and is now routinely begun in all children with severe hemophilia A. Primary prophylaxis is composed of regular, weight based, infusions of recombinant factor VIII products, starting at an early age, to prevent joint and muscle damage and future disability. In addition, early initiation of home treatment (self-infusion of recombinant factor VIII) is important for good quality of life and to halt bleeding quickly following possible injury or spontaneous bleeding.

Manco-Johnson MJ et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007;357:535-44.

Question 35

A 22 year old female is referred to your clinic for a lifelong history of easy bruising and heavy menstrual bleeding starting at menarche.

1. Is this bleeding history significant? Are there any clinical prediction rules that may help in defining pre-hemostatic test probability?
   Yes, this bleeding history is significant. Heavy menstrual bleeding starting at menarche and a low ferritin are two very sensitive markers that suggest the significance of a bleeding history.
   There are numerous bleeding questionnaires that have been developed and validated to aid in the diagnosis of von Willebrand disease. Please see below for the history of bleeding questionnaires that help in the diagnosis of bleeding disorders.
   These bleeding questionnaires have a very powerful negative predictive value and can, with a negative score, eliminate the need for von Willebrand screening. This is extremely important as the diagnosis of von Willebrand is rife with confounding factors, including pre-analytical laboratory variables that can lead to its excessive and improper diagnosis.
2. She is found to have von Willebrand disease on hemostatic testing. What is von Willebrand disease?
   Von Willebrand disease (VWD) is also inherited, but unlike hemophilia, it is not gender linked. It is inherited predominantly in an autosomal dominant fashion and has a prevalence of 1%. There are exceptions, however, as well as variable penetrance in some subtypes.
3. What is the initial screen for von Willebrand disease? What are the subsequent tests required to further define the diagnosis?
   VWD presents as bleeding in the mucous membranes and also as bleeding in joints/muscles among the few individuals with a severe form of the disorder.
   There are 3 broad types of VWD:
   1. Type 1 (partial quantitative defect). Type 1 VWD is the most common form.
   2. Type 2 (qualitative defect),
   3. Type 3 (complete qualitative absence).

   VWD is caused by insufficient or impaired function of a protein called von Willebrand factor (VWF). VWF is synthesized by endothelial cells and megakaryocytes. It is stored in the Weibel-Palade bodies of endothelial cells and alpha granules of platelets. VWF exists in various forms – from dimers to larger multimers. The larger the VWF molecule, the more active it is in primary hemostasis – i.e. the better it helps with platelet function.
   VWF has two major hemostatic roles:

   • Platelet adhesion and aggregation,
   • Chaperoning and prolonging the half-life of coagulation factor VIII.

   VWF is therefore important for both primary and secondary hemostasis.

Sadler, JE. Low von Willebrand factor: sometimes a risk factor and sometimes a disease. Hematology Am Soc Hematol Educ Program. 2009:106-12. doi: 10.1182/asheducation-2009.1.106.