Module 5 - Hematology
N609

Definition: thromboembolic event occurring in the venous system
Manifestations: deep vein thrombosis (DVT) or pulmonary embolism (PE)
Virchow triad
Venous stasis (sluggish blood flow)
Vascular endothelial wall injury
Hypercoagulability (propensity for increased blood clotting)

A practitioner is examining a patient for risk factors for DVT. Which factor is considered reversible?
A. Hematologic disease
B. Antiphospholipid antibodies
C. Factor V Leiden
D. Estrogen therapy

D. Estrogen therapy
Rationale: Trauma, surgery, pregnancy, estrogen therapy, chemotherapy, prolonged or transient immobility, fractures, central venous catheters, obesity, long-haul air travel are reversible risk factors for venous thromboembolism (VTE) and PE. Hematologic disease and antiphospholipid antibodies are acquired risk factors. Factor V Leiden is an inherited disorder and risk factor.

Proximal DVT and PE
Malignancy
Antiphospholipid antibody syndrome
Male sex
Persistent positive d-dimer (checked 3 weeks to 2 months following cessation of anticoagulation)
Residual thrombosis

Definition
Cardiac arrhythmia characterized by loss of coordination of electrical and mechanical activity in the atria.
Thrombi can form in the left atrial appendage due to impaired ventricular filling and incomplete emptying of the atria.
Major complications of AF include stroke, heart failure, dementia, and death.

Palpitations
Chest discomfort
Shortness of breath
Weakness
Hypotension
Dizziness
Syncope

Preventing transient ischemic attack (TIA) and stroke with anticoagulant drugs
Restoring and maintaining sinus rhythm in selected patients
Controlling the ventricular heart rate

Stabilize (monitor heart rate, blood pressure, respiratory status, and medication)
Assess (fluid and electrolyte status, medication management, risk factor identification and modification)
Label/treat (arrhythmia management, reducing anxiety, anticoagulation management)
Educate (disease process, anticoagulation teaching, prescribed medications)

Caused by degenerative valve disease due to increasing life spans and rheumatic heart disease.
Confers a high risk of systemic embolism and antithrombotic therapy, antiplatelet therapy, anticoagulation, or a combination of antiplatelet and anticoagulation is warranted in most patients.
Two types of heart valves: mechanical and bioprosthetic.

Role of clotting cascade
Thrombotic process
Hypercoagulable states

Erythema
Pain
Swelling
Venous distention
Warmth in the affected leg
Levels of d-dimer are elevated (>500 mcg/L)
Methods used for detecting DVT: contrast-enhanced venography, compression ultrasonography (CUS), and MRI

Palpitations
Chest discomfort
Shortness of breath
Fatigue
Hypotension
Dizziness
Syncope

Stroke is characterized by a sudden or progressive onset of focal neurologic signs due to an inadequate blood supply to the brain.
The most common presenting stroke symptom is tingling, numbness, and weakness or paralysis on one side of the body. Incoordination, aphasia, dysarthria, changes in mental status or loss of consciousness, and visual disturbances also can occur.
Most often, the deficits are confined to one side of the body, right or left.

Symptoms vary depending on the valve that is affected.
In aortic stenosis, the cardinal symptoms are dyspnea, angina, syncope, and heart failure.
Aortic regurgitation is often asymptomatic.
Dyspnea is the hallmark symptom of mitral stenosis.
Mitral regurgitation also progresses slowly and may be asymptomatic for many years.
Each valvular disorder is associated with a characteristic murmur.

Preventing the development of a stroke is the primary goal of antithrombotic therapy in patients with AF, prosthetic heart valves, and in those with a history of cardioembolic stroke.
Anticoagulation treatment in patients with existing DVT/PE is initiated to prevent extension of the thrombus; thromboembolic complications, including postthrombotic syndrome; and development of a new thrombus.

Anticoagulation prophylaxis after orthopedic surgery is initiated with aspirin or anticoagulation to decrease the risk of DVT or PE.
The goals of antiplatelet therapy are to prevent and treat ischemic strokes from noncardioembolic sources.

A practitioner is prescribing an anticoagulant for a patient with atrial fibrillation. What is the primary goal of this treatment?
A. Preventing stroke
B. Preventing PE
C. Preventing valve replacement
D. Promoting coagulation

A. Preventing stroke
Rationale: Preventing the development of a stroke is the primary goal of antithrombotic therapy in patients with AF, prosthetic heart valves, and in those with a history of cardioembolic stroke.

Injectable agents unfractionated heparin (UFH) and low molecular weight heparins (LMWHs) (e.g., enoxaparin)
Oral vitamin K antagonist (VKA) warfarin
Direct-acting oral anticoagulants (DOACs) dabigatran etexilate
Oral factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban)

Active major bleeding
Recent intracranial hemorrhage
Intracranial mass with high bleeding risk
End stage live disease
Severe thrombocytopenia
Recent trauma or traumatic surgery
Use in the immediate postoperative period after central nervous system (CNS) or ocular surgery
Presence of spinal catheters and aneurysms

Greater bioavailability with subcutaneous administration
Longer duration of anticoagulant effect, allowing for once-daily or twice-daily dosing
High degree of correlation between anti-Xa and body weight, allowing for fixed dosing
Less intensive nursing care and less intensive laboratory monitoring
More predictable anticoagulant response, permitting use in the outpatient setting

INR GOAL 2.0 TO 2.5
Patients with a disease-specific anticoagulation goal of 2.0-3.0 (see below) who also are taking concomitant aspirin and a P2Y12 inhibitor.
INR GOAL 2 TO 3
Prophylaxis of venous thrombosis
Treatment of venous thrombosis
Treatment of PE

INR GOAL 2 TO 3 (cont.)
Prevention of systemic embolism
Stroke prevention in atrial fibrillation
Tissue (bioprosthetic) heart valves
Mechanical prosthetic heart valves (bileaflet valves; St. Jude Medical, Medtronic Hall)
Valvular heart disease
Hypercoagulable conditions (antiphospholipid antibodies with lupus anticoagulant)-if no history of thrombotic events

INR GOAL 2.5 TO 3.5
Mechanical prosthetic heart valves (caged ball, tilting disk)
Hypercoagulable conditions (antiphospholipid anti-bodies with lupus anticoagulant)-if a history of thromboembolic events with INR of 2 to 3

Have any warfarin doses been missed in the past 3 to 5 days?
Have extra warfarin tablets been ingested?
Is the patient taking a warfarin regimen other than prescribed?
Is the patient experiencing bleeding problems?
Is the patient experiencing thromboembolic complications?

Have any new medications (prescription, over the counter, herbal) been started, deleted, or changed from the patient's medication regimen?
Has the patient's underlying condition changed, as in acute congestive heart failure exacerbation or worsening renal or hepatic impairment?
Has the patient had a recent acute febrile or GI illness?
Has thyroid status changed or has a malignancy been diagnosed?

While the number of prescriptions of DOACs is rapidly increasing in the United States, about half of all patients requiring chronic anticoagulation are still prescribed warfarin (Barnes GD et al., 2018).
However, it has numerous drug-drug interactions very narrow therapeutic index, and requires routine laboratory monitoring of the INR at least every 4 to 12 weeks
Warfarin is appropriate for patients with end-stage kidney disease because information on DOAC safety from clinical trials of DOACs is limited.

Lack of a specific antidote for reversal of edoxaban
Higher acquisition cost
Potentially a faster offset of action so that adherence is key to sustained effect

Bleeding is the most worrisome adverse event associated with antithrombotic therapy. In patients with AF, DOACS reduce the risk of major bleeding compared to warfarin
In addition to the intensity of anticoagulation, the other major factors that determine bleeding risk include individual patient characteristics such as elderly age, chronic kidney disease, liver disease, a prior history of stroke (for patients with AF), a labile INR (for patient taking warfarin), anemia, active cancer, uncontrolled HTN, ethanol use, concomitant antiplatelets (such as aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), P2Y12 inhibitors such as clopidogrel, prasugrel, and ticagrelor) and concomitant use of selective serotonin reuptake inhibitors (such as sertraline, fluoxetine, and citalopram), ethanol intake, as well as a longer duration of therapy

When the INR is elevated, management depends on the patient's potential risk of bleeding, whether the patient is actively bleeding, and the INR level.
Treatment options include simply omitting one or more warfarin doses with more frequent INR testing or administering vitamin K.

Currently, there are no available antidotes for edoxaban-associated bleeding.
Idarucizumab, a humanized monoclonal antibody fragment, binds to dabigatran with a higher affinity than thrombin thus neutralizing dabigatran's anticoagulant effect.
The half-life of idarucizumab is 45 minutes to 70 minutes.
It may be administered to treat major bleeding or to reverse anticoagulant effects for surgery or medical procedures.

Excessive anticoagulation with UFH can be reversed with IV protamine sulfate, which is high in arginine and is cationic binding tightly to heparin, which is highly anionic, thus reversing the anticoagulant effect

There is no proven method for reversing excessive anticoagulation occurring with LMWHs, although consensus guidelines provide dosing recommendations for using protamine and it has been found useful in some, but not all, coagulopathic patients (Witt et al., 2018).
Preliminary data suggests that andexanet alpha may reverse enoxaparin coagulopathy (Dobesh et al., 2019).

Antiplatelet agents that have been used in the prevention and treatment of ischemic stroke are aspirin, aspirin/dipyridamole (Aggrenox), and the P2Y12 inhibitor clopidogrel (Plavix). Aspirin has been studied in primary and secondary prevention of VTE.

Treatment of DVT or PE
Prophylaxis of DVT and PE
Secondary prevention of noncardioembolic ischemic stroke and TIA
Stroke prevention in atrial fibrillation
Prophylaxis against systemic embolism in patients with prosthetic heart valves

Genomics
Nondrug therapy

Oral anticoagulant patient education
Nutrition education for warfarin

Thromboembolic disease and patients with risk factors for thromboemboli are frequently encountered in the ambulatory population.
An understanding of the pathogenesis of these conditions and underlying patient risk factors, along with the clotting cascade, is essential for determining appropriate treatment.
The indications for anticoagulation continue to expand, and treatment for some conditions has now shifted to the outpatient setting.

Anticoagulation practices are an important component of quality metrics and patient safety practices for hospitalized patients.
Practitioner must be aware of anticoagulation management strategies for prevention and treatment of VTE and SPAF, and the prevention of systemic thromboembolism in patients with prosthetic heart valves.

Definition: condition in which there is a decrease in the number of red blood cells (RBCs) or hemoglobin in the blood
Effects: reduced ability to carry oxygen to meet physiologic needs, which varies by age, sex, altitude, and pregnancy status
Diagnostic criteria: values that are more than two standard deviations below the mean
The World Health Organization (WHO) criteria for anemia in men and women are <13.0 and <12.0 g/dL, respectively

Blood loss
Nutritional deficiency
Malabsorption syndromes
Occurring concurrently with inflammation or malignancy
Inherited as in sickle cell disease, thalassemia, or hemoglobinopathy

Hemoglobin: Adult male: 13.3 to 16.2 g/dL; Adult female: 12.0 to 15.8 g/dL
Hematocrit: Adult male: 38.8% to 46.4%; Adult female: 38.8% to 46.4%
Reticulocyte count: Adult male: 0.8% to 2.3% RBCs; Adult female: 0.8% to 2.0% RBCs
WBC (leukocyte): 3.54 to 9.06 L
Mean corpuscular hemoglobin (MCH): 26.7 to 31.9 pg
Mean corpuscular volume (MCV): 79 to 93 fL

Mean platelet volume (MPV): 9.0 to 12.95 fL
Mean corpuscular hemoglobin concentration (MCHC): 32.3 to 35.9 g/dL
Platelet: 165 to 415 mn
Ferritin: Adult male: 15 to 400 ng/mL; Adult female: 10 to 200 ng/mL
Vitamin B12: 200 to 600 pg/mL
Folate: 3 to 16 ng/mL

A practitioner is examining an adult male patient's lab values. Which value is not within the normal range?
A. Hemoglobin of 15.0 g/dL
B. Hematocrit 45.2% RBCs
C. Reticulocyte count: 0.53% RBCs
D. WBC 4.54 L

C. Reticulocyte count: 0.53% RBCs
Rationale: Reticulocyte count of 0.53% RBCs for an adult male is low. The normal range is 0.8% to 2.3% RBCs.

Rapid onset of anemia
Cardiorespiratory symptoms (tachycardia, light-headedness, breathlessness)
Anemia of a chronic nature
Vague symptoms including fatigue, weakness, headache, vertigo, faintness, sensitivity to cold, pallor, and loss of skin tone

History
Recent and past infections, malignancy, renal disease, and a history of autoimmune disease
Physical (ROS)
Weight loss or weight gain, fever, chills or night sweats, change in bowel habits and black tarry stools; determine if acquired or inherited
Laboratory testing
Complete blood count (CBC)

Causes
Massive hemorrhage associated with spontaneous or traumatic rupture
Incision of a large blood vessel
Erosion of an artery by a lesion
Failure to maintain normal hemostasis
Immediate therapy: hemostasis, restoration of blood volume, and treatment of shock; blood transfusion

Patients predominantly make hemoglobin S that is present in red blood cells.
When the erythrocyte in patient with sickle cell disease becomes stressed, the erythrocyte loses its oxygen causing the cell integrity to be lost.
These cells form long, stiff rod-like structures that bend the erythrocyte into a sickle shape, which get stuck in the blood vessels and cut of blood supply to organs.
Significant damage to the endothelium of the arterial and venous circulation leads to a sickle cell crisis.

Focuses on primary prevention and treatment of the complication as well as a potential cure.
Children with SCD should be immunized against S. pneumoniae, H. influenzae type B, hepatitis B virus, and influenza.
All individuals should be immunized as recommended by the Advisory Committee on Immunizations Practices.
Patients are maintained on folic acid supplementation, 1 mg/d, because of accelerated erythropoiesis.

Hydroxyurea
Use: prophylaxis treatment to reduce the number of crises
Action: increases hemoglobin F levels, water content of RBCs, deformability of sickled cells, and alters the adhesion of RBCs to endothelium
Starting dose: Adults: 15 mg/kg/d; chronic kidney disease: 5 to 10 mg/kg/d; infants and children: 20 mg/kg/d

Oxbryta (voxelotor)
Acetaminophen
NSAIDs

A practitioner is prescribing hydroxyurea for a child with sickle cell disease. What is the recommended dosage for this patient?
A. 5 mg/kg/d
B. 10 mg/kg/d
C. 15 mg/kg/d
D. 20 mg/kg/d

D. 20 mg/kg/d
Rationale: Starting dosage for infants and children is 20 mg/kg/d. The starting dose of hydroxyurea for adults is 15 mg/kg/d (round up to the nearest 500 mg). For a patient with chronic kidney disease, the dose is adjusted to 5 to 10 mg/kg/d.

Diagnosis: made by low hemoglobin and iron stores
Causes: insufficient iron intake, inadequate absorption from the GI tract, and increased iron demands
Diagnostic criteria: low serum iron and ferritin concentrations and a high total iron-binding capacity (TIBC)
Treatment: depends on underlying cause; start with 100 to 200 mg of elementary iron; Children: 3 to 6 mg/kg

Cause: reduced EPO production by the kidney; anemia occurs when the glomerular filtration rate (GFR) declines below 60 mL/minute
Drug therapy
Multivitamin, iron supplementation, treating reversible causes of deteriorating renal function
Oral phosphorus-binding agents, calcium carbonate, and calcium acetate to treat hyperphosphatemia. Vitamin D or vitamin D analogs to treat secondary hyperparathyroidism

Recombinant EPO (epoetin, Epogen, Procrit); zidovudine administration (in HIV-infected patients), and chemotherapy administration.

A practitioner is prescribing drug therapy for a patient to treat hyperparathyroidism secondary to anemia of chronic renal failure. What is an agent of choice for this patient?
A. Oral phosphorus-binding agents
B. Vitamin D
C. Calcium carbonate
D. Calcium acetate

B. Vitamin D
Rationale: Vitamin D or vitamin D analogs are used to treat hyperparathyroidism secondary to anemia of chronic renal failure. Oral phosphorus-binding agents, calcium carbonate, and calcium acetatea are used to treat secondary hyperphosphatemia.

Chronic infections
Chronic inflammation
Malignancies
Alcoholic liver disease
Heart failure; ischemic heart disease
Thrombophlebitis
COPD

Definition: thalassemias are hereditary disorders of hemoglobin synthesis, which are considered among the hypoproliferative anemias.
Treatment: patients with severe thalassemia are maintained on a regular transfusion schedule and receive folate supplementation.
Iron chelation therapy with deferoxamine mesylate may be used when transfusions result in tissue iron overload.

Cause: disorder of impaired DNA synthesis; considered a macrocytic anemia and may arise because of genetic or acquired abnormalities
Diagnostic criteria: serum vitamin B12 assay
Therapy: parenteral administration of vitamin B12
Pernicious anemia is typically treated with parenteral (i.e., intramuscular or deep subcutaneous) cyanocobalamin in a dose of 1,000 mcg (1,000 mcg, 1 mg) every day for 1 week followed by 1 mg every week for 4 weeks.

Action: results in the development of large functionally immature erythrocytes (megaloblasts)
Causes: inadequate intake, inadequate absorption, inadequate utilization, increased requirement, and increased excretion of folate
Symptoms: weakness, fatigue, difficulty concentrating, irritability headache, shortness of breath, palpitations
Treatment: folic acid 1 mg daily

Definition: pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate and with no increase in reticulin
Causes: direct stem cell injury from radiation, chemotherapy (alkylating agents), antimetabolites, antimitotics, toxins (benzenes), or pharmacologic agents
Diagnostic criteria: CBC, platelet counts, bone marrow aspirate and biopsy, MRI
Therapy: RBC transfusions, platelets, antibiotics, HSCT, immunosuppression therapy

Special populations:
Pediatric
Geriatric
Women
Patient education
Nutrition
CAM

All patients with anemia are encouraged to limit the use of alcohol, to avoid tobacco, to exercise, and to consume a diet of meat, poultry, fish, and fresh fruits and vegetables.
To prevent deficiency, all patients are encouraged to eat fortified foods (fortified cereals, dairy products) or take supplements as prescribed by their physician.

Arcangelo, V. (2022). Pharmacotherapeutics for Advanced Practice: A Practical Approach. 5th ed.
Wolters Kluwer. Philadelphia, PA