Chapter 33: Hematologic Disorders

Population

• –Adult patients with cancer and anemia.

Recommendation

American Society of Hematology/American Society of Clinical Oncology (ASH/ASCO) 2010

• –Approach to anemic cancer patients

  • History, physical exam, and diagnostic studies to exclude other causes of anemia aside from chemotherapy or malignant marrow infiltration.

  • The FDA label now limits the use of Erythrocyte Stimulating Agents (ESA) ONLY to anemic cancer patients receiving chemotherapy with palliative intent. (N Engl J Med. 2007;356:2448) ESA is NOT to be used in patients with curable malignancies or in patients with cancer not on chemotherapy. Side effects of thrombosis and potentially increased cancer growth should be discussed with the patient. (J Natl Cancer Inst. 2013;105:1018)

  • Correct iron deficiency anemia: if iron saturation is <20% or ferritin <20, then PO/IV iron supplementation of elemental iron 40–195 mg per daily.

  • Epoetin and darbepoetin are equal in efficacy.

  • ESA should not be used if hemoglobin >10 g/dL. The main benefit of ESA is to reduce transfusion need. (Br J Cancer. 2010;102:301)

  • FDA-approved starting dose of epoetin is 150 U/kg 3 times/wk or 40,000 U weekly. For darbepoetin the dose is 2.25 µg/kg weekly or 500 µg every 3 wk subcutaneously.

  • Stop ESAs at 6–8 wk if no evidence of a response. Check for underlying tumor progression, iron deficiency, or other causes of anemia.

  • Dose of ESAs should be lowest concentration needed to avoid transfusion. Keep hemoglobin <12.

  • Periodic monitoring of ferritin and iron studies is recommended since ESAs will not improve hemoglobin if the patient is iron deficient.

  • Use of ESAs in lower-risk myelodysplastic syndrome to decrease transfusions is approved if erythropoietin level is <500 mµ/mL. The use of low-dose filgrastrin (100 μg once or twice/wk) will increase responsiveness to ESAs.

Sources

• –Aapro M, et al. Management of anaemia and iron deficiency in patients with cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2018;29(suppl 4):iv96–iv110.

• –ASH/ASCO guidelines update on use of epoetin and darbepoetin. Blood. 2010;116:4045-4059.

• –Schrier S, Steensma D, Loprinzi L. Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer. Uptodate.com. 2018.

Comments

1. Important facts about ESAs

   1. Early studies raising hemoglobin level to >12 g/dL resulted in significant increased risk of venous thromboembolus.

   2. Beware of clot risk when using ESAs with other thrombophilic drugs (tamoxifen, BCP, lenalidomide).

   3. The molecular structure of darbepoetin increases its half-life, allowing for less frequent injections.

   4. Fifty percent of cancers will have erythropoietin receptors on the cell surface. It has NOT been proven that ESAs’ interaction with cell surface receptors leads to cellular proliferation.

   5. When patients stop chemotherapy for any reason, ESAs must be stopped and transfusion therapy substituted according to FDA guidelines.

   6. The addition of intravenous iron to ESAs will increase hemoglobin more rapidly since iron is sequestered in the reticuloendothelial system in the cancer-associated anemia of chronic disease. (N Engl J Med. 2005;352:1011)

   7. ESAs are widely used in chronic renal insufficiency, reducing need for transfusion significantly. Iron is often given to these patients to keep ferritin level between 100 and 500 ng/mL and transferrin saturation 20%–50%. (N Engl J Med. 2010;362:3)

   8. RBC transfusion should be considered if Hgb <8 or if severe anemia-related symptoms occur.

Population

• –Adults presenting to ED with suspected or known carbon monoxide poisoning.

Recommendations

• –Do not use noninvasive carbon monoxide measurements to diagnose carbon monoxide poisoning.

• –Use hyperbaric oxygen or high-flow oxygen therapy for acute carbon monoxide poisoning.

• –Recommend obtaining an EKG and cardiac biomarkers to identify acute myocardial injury in patients with moderate-to-severe carbon monoxide poisoning.

Source

• –Wolf SJ, Maloney GE, Shih RD, Shy BD, Brown MD; American College of Emergency Physicians. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute carbon monoxide poisoning. Ann Emerg Med. 2017;69(1):98-107.

Population

• –Adults ≥19 y of age.

Recommendations

British Colombia Medical Services Commission 2012

• –Who to test:

  • Unexplained neurologic symptoms including paresthesias, numbness, poor motor coordination, and cognitive and personality changes.

  • Macrocytic anemia with oval macrocytes, hypersegmented neutrophils, or pancytopenia.

  • Elderly (≥75-y-old), history of inflammatory bowel disease, gastric or small bowel resection, prolonged vegan diet, specific medications (histamine receptor antagonist, proton pump inhibitors, and metformin), history of Helicobacter pylori infection.

• –How to test:

  • Complete blood count, peripheral blood smear, and serum B₁₂ level.

  • <220 pmol/L is most recognized cut-off with increasing probability of clinical deficiency. If B₁₂ <75 pmol/L, clinical signs and symptoms of B₁₂ deficiency, then diagnosis is highly likely. In borderline patients with normal renal function, methylmalonic acid levels will be elevated in B₁₂-deficient patients.

  • Elevated LDH, indirect bilirubin, and low haptoglobin are common findings.

• –Treatment—Early

  • Therapy of cobalamin deficiency is important because neurologic symptoms may be irreversible if treatment is delayed.

  • Oral crystalline cyanocobalamin is as effective as parenteral B₁₂. 1000 μg/d is the recommended dose but parenteral administration (1000 μg/d for 5–10 d) should be given to patients with neurological symptoms.

  • In these patients 1000–2000 μg/d given orally should follow parenteral administration.

  • Retest serum cobalamin levels after 2–4 mo to ensure they are in the normal range.

Sources

• –Medical Services Commission. Cobalamine (vitamin B₁₂) deficiency investigation and management. Victoria British Colombia: Medical Services Commission; 2012.

• –Blood. 2008;112:2214-2221.

• –Blood. 2017;129:2603.

• –Blood. 2018;131:505-514.

Comments

1. Pernicious anemia (the most common cause of B₁₂ deficiency) is an autoimmune illness with antibodies to parietal cells and intrinsic factor resulting in gastric atrophy and malabsorption of food-derived B₁₂.

2. Cobalamin is found exclusively in animal products such as meat, seafood, dairy products, and eggs. Consider supplemental oral B₁₂ in patients who are long-term vegans.

3. Independent of the etiology of B₁₂ deficiency, oral B₁₂ (1000–2000 mg) daily will correct lower B₁₂ levels.

4. With pure B₁₂ deficiency the mean corpuscular volume (MCV) is usually >110. If iron deficiency is also present due to bleed or atrophic gastritis, the MCV can be <100.

5. Patients with elevated MCV who are folate deficient must have B₁₂ deficiency ruled out since treatment with folate in patients with B₁₂ deficiency will accelerate peripheral neuropathy.

6. The incidence of B₁₂ deficiency in the elderly (>70-y-old) is 5%–10%.

7. Less frequent causes of B₁₂ deficiency include Helicobacter pylori infection, Diphyllobothrium latum infection, nitrous oxide exposure, alcoholism, Zollinger–Ellison syndrome, small bowel diverticulum, and following gastric bypass surgery.

8. Drugs that can cause folate deficiency and B12 deficiency include trimethoprim, pyrimethamine, methotrexate, and phenytoin.

9. When treating B₁₂ and folate deficiency, the MCV may decrease due to acquired iron deficiency as iron is incorporated into red cell precursors in response to B₁₂ and/or folate therapy.

Population

• –Complete remission of DLBCL following treatment with negative PET-CT scan.

Recommendations

NCCN 2016

1. Stages I and II (Limited stage disease):

   • History and physical exam and labs:

     • Initial: Hepatitis B, uric acid, HIV.

     • Recurrent: CBC, metabolic panel + LDH every 3–6 mo for 5 y, then yearly as clinically indicated.

   • Imaging:

     • Repeat CT or PET scan only as clinically indicated (symptoms, palpable nodes, or abnormal labs—especially increased LDH).

     • If recurrence is suspected, re-biopsy is mandatory to guide salvage therapy.

   • Treatment options:

     • Combined modality: 3 cycles of anti-CD20 rituximab and field radiation.

     • Full-course chemotherapy: 6–8 cycles of systemic chemotherapy + rituximab.

2. Stages III and IV (Advanced stage disease):

   • History and physical with labs:

     • Initial: Hepatitis B, uric acid, HIV.

     • Recurrent: CBC, metabolic panel + LDH every 2–4 mo for 5 y, then yearly or as clinically indicated.

   • Imaging​​​​​: Controversial—either CT scans every 6 mo or only when signs or symptoms are suggestive of recurrence.

   • Treatment options:

     • Observation or consider radiation therapy (RT) to initial area of bulky (>10 cm) disease.

     • High-dose chemotherapy + rituximab.

     • Autologous stem cell rescue in very high-risk patients who have Stage IV disease and a significant chance of relapse.

Sources

• –Mayo Clin Proc. 2015;90:1574-1583.

• –J Clin Oncol. 2014;32:3039-3059.

• –Freedman A, Friedberg J. Initial treatment of advanced stage diffuse large B cell lymphoma. www.uptodate.com. 2018.

Comments

1. Lymphoma facts

   1. DLBCL most common non-Hodgkin’s lymphoma (NHL)—30%.

   2. Follicular lymphoma second most common at 20%.

   3. 71,000 cases of NHL with 19,000 deaths yearly. Total number of NHL diagnosis is increasing by 1%–2% per year.

2. Ann Arbor staging system

   1. Stage I—single nodal group either side of diaphragm.

   2. Stage II—more than 1 nodal group involvement either side of diaphragm.

   3. Stage III—nodal groups on both sides of the diaphragm.

   4. Stage IV—disseminated disease to bone marrow and/or visceral organs.

3. β symptoms include fever, night sweats, and weight loss.

4. Bulky disease (>10 cm) increases risk of recurrence.

5. There has been a reduction in frequency of surveillance CT scans due to concern about increased radiation exposure. (JAMA.2012;307:2400)

6. Monitor for late events—secondary cancers, cardiovascular disease, hypothyroidism, and fertility issues.

7. Bone marrow injury may evolve to myelodysplasia and acute myeloid leukemia.

8. Always biopsy recurrent disease—10%–15% will be follicular lymphoma with indolent biology.

9. CNS prophylaxis in aggressive DLBCL (testis, sinus, bone marrow)—intrathecal vs. high-dose methotrexate with rescue.

Population

• –Adults.

Recommendations

British Society of Gastroenterology

• –Scope of Problem

  • Iron deficiency anemia (IDA) is the most common cause of anemia and occurs in 2%–5% of adult men and postmenopausal women in the developed world.

  • More than 25% of the world’s population is anemic with one-half attributed to iron deficiency. (N Engl J Med. 2015;372:1832)

• –Diagnosis

  • Hgb <13 g/dL in men, <12 g/dL in nonpregnant women. (Gut. 2011)

  • Serum ferritin <30, iron transferrin saturation <10%, and hypochromic, microcytic RBCs on peripheral smear. MCV is usually >80 until hemoglobin drops to <10 g/dL; random distribution of width (RDW) is elevated. (N Engl J Med. 2005;352:1741-1744) (N Engl J Med. 1999;341:1986-1995)

• –Clinical Evaluation

  • Upper and lower gastrointestinal investigations (esophagogastroduodenoscopy and colonoscopy preferred) should be done in all postmenopausal females and all male patients unless there is a history of recent non-GI significant blood loss. (Am J Med. 2001;111:439-445)

  • Fecal occult blood testing is of no benefit and rectal exam is seldom contributory in IDA. Iron deficiency without significant anemia should also be worked up with GI evaluation in postmenopausal women and men >40-y-old. (N Engl J Med. 1993;329:1691-1695)

  • If the patient has undergone gastrectomy, upper and lower GI investigation is indicated in those >40 y. If upper and lower GI tracts are normal, small bowel visualization is indicated if the patient has symptoms of small bowel disease and/or continued fecal occult blood-positive stools. (Best Pract Res Clin Haematol. 2005;18:319-322)

  • All patients should be screened for Celiac disease with IgA-tissue transglutaminase. (Gut. 2011) Evaluate urine for blood. (Gut. 2011) Test for Helicobacter pylori with eradication if present. (Gut. 2011)

• ‒Iron Replacement Therapy

  • Ferrous sulfate (65-mg elemental iron) should be administered 2–3 times a day depending on tolerance. Taking iron 15–30 min before a meal with orange juice or 500 mg of vitamin C will enhance absorption. Treatment should be continued for 4–8 mo to fully replete iron stores.

  • 20%–25% of patients on iron therapy will have GI side effects (abdominal bloating, pain, nausea, vomiting, diarrhea/constipation). Reducing the elemental iron concentration of each dose may avoid side effects.

  • If intolerant of iron, noncompliant, continued losses despite oral therapy, or have diminished iron absorption, intravenous iron (dosing below) should be given to replete iron stores and correct the anemia.

  • Transfusion of RBC should be reserved for cardiovascular instability. (Gut. 2011)

• –Refractory Iron Deficiency

  • In patients who have been compliant but do not correct their iron deficiency with oral iron must have further evaluation. Many gastric bypass patients have reduced iron absorption due to bypass of the duodenum where the majority of iron absorption takes place.

  • Occasionally, patients have significant continued blood loss for which oral iron is insufficient to maintain iron stores. Other possible causes such as celiac sprue, H. pylori infection, and autoimmune gastritis must be evaluated and treated. (Haematologica. 2005;90:585-595)

  • Antacids and protein pump inhibitors will also reduce iron absorption. Hereditary iron-refractory iron deficiency syndrome is an autosomal recessive disorder caused by mutations affecting iron transport.

Sources

• –http://www.guideline.gov/search/search.aspx?term=iron+deficiency+management.

• –N Engl J Med. 2015;372:1832.

• –Gut. 2011;60:1309-1316.

Comments

• Clinical Correlates

  1. Symptoms of IDA: weakness, headache, irritability, fatigue, exercise intolerance, and restless leg syndrome. Symptoms may occur without anemia in patients with iron depletion (ferritin <30 ng/mL). As many as 40% of patients with IDA will experience pica (appetite for clay, starch, and paper products) and/or pagophagia (craving for ice) which resolves rapidly with iron repletion.

  2. Rarely, in severe iron deficiency, dysphagia and esophageal webs (Plummer–Vinson syndrome) occur as well as koilonychias (spoon nails), glossitis with decreased salivary flow, and alopecia also occur with severe prolonged IDA.

  3. Infrequent causes of iron deficiency: intravascular hemolysis (especially paroxysmal nocturnal hemoglobinuria and microangiopathic hemolytic anemia), pulmonary hemosiderosis, and congenital IDA (germ-line mutation in the TMPRSS6 gene which leads to a reduction in iron absorption and mobilization).

  4. Rule out other hypochromic, microcytic anemias (see Table I). Diagnosing iron deficiency in patients who also have anemia of chronic disease (ACD) is difficult. Circulating transferrin receptor (sTFR) is elevated when iron deficiency is present and a high sTFR/ferritin index is consistent with concurrent IDA and ACD. A bone marrow examination with absent stainable iron stores, although invasive, will also confirm a diagnosis of IDA in the presence of ACD. Recombinant erythropoietin is not effective in treating anemia in patients who are iron deficient. (N Engl J Med. 2014;371:324)

  5. Oral iron therapy: 15–30 min before a meal with 250–500 mg of vitamin C or a glass of orange juice.

     1. 20%–25% of patients will have GI side effects including abdominal pain, nausea, constipation, and diarrhea.

     2. Side effects are related to the amount of elemental iron delivered with each dose.

     3. Ferrous sulfate that contains 65 mg of elemental iron. If GI side effect, lower the elemental iron intake by giving ferrous gluconate (28–36 mg of elemental iron) or titrating liquid ferrous sulfate (44 mg iron per 5 mL). (Blood. 2014;123:326-333) (Transfusion. 2008;48:988-995)

  6. IV iron therapy:

     1. Effect: modest early increase in reticulocytes vs. oral iron and 8–10 wk for hemoglobin levels to normalize.

     2. Iron sucrose (Venofer®) is effective and has a 15-fold reduction in the risk of anaphylaxis compared to iron dextran. Dose 150–200 mg once or twice a week until the calculated iron deficit is administered.

     3. Ferric gluconate complex (Ferrlecit®) is similar to iron sucrose.

     4. Ferumoxytol (Feraheme®) is composed of iron oxide nanoparticle and is approved for use only in patients with renal failure.

     5. Ferric carboxymaltose (Ferinject®) is the newest IV iron option with 1000 mg elemental iron weekly with more rapid infusion times. Low phosphate levels have been reported. Benefits in patients with iron deficiency and heart failure.

     6. Iron dextran risk of anaphylaxis is significant and not recommended. (Ann Int Med. 2010;152:4-5)

  7. If there is no response to iron supplement, do iron absorption test: check a baseline iron level and then a second iron level 2–4 h after ingesting a single 325 mg ferrous sulfate tablet with water. An increase in the iron level of at least 100 µg/dL indicates adequate absorption.

  8. Some patients malabsorb iron: celiac disease (IgA anti-tissue transglutaminase antibody, duodenal biopsy), H. pylori infection of the stomach (dx by stool antigen, urea breath test, gastric biopsy), and autoimmune gastritis (gastrin level, intrinsic factor, and parietal cell antibodies, gastric biopsy) and congenital iron deficiency (recessive germ-line mutation in TMPRSS6). (N Engl J Med. 2012;366:376-377) (Arch Int Med. 2000;160:1229-1230) (Blood. 2014;123:326-333) (Am Fam Physician. 2013;87:98)

Population

• –Adult men and women with cancer.

Recommendation

ASCO Clinical Practice Guidelines

–Most hospitalized patients with active cancer require thromboprophylaxis throughout hospitalization. Data are inadequate to support routine thromboprophylaxis in patients for minor procedures or short chemotherapy infusions.

• Routine thromboprophylaxis is not recommended for ambulatory patients with cancer. It may be considered for selected high-risk patients.

• Patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and/or dexamethasone should receive prophylaxis with either low-molecular-weight heparin (LMWH) or low-dose aspirin to prevent venous thromboembolism (VTE).

• Patients undergoing major cancer surgery should receive prophylaxis starting before surgery and continuing for at least 7 to 10 d after discharge (30-mg enoxaparin bid).

• Extending postoperative prophylaxis up to 4 wk should be considered in those undergoing major abdominal or pelvic surgery with high-risk features.

• LMWH is recommended for the initial 5–10 d of treatment of established deep vein thrombosis and pulmonary embolism as well as for long-term secondary prophylaxis for at least 6 mo. If the cancer remains active, LMWH should be given indefinitely.

• Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE but trials are ongoing to prove benefit.

• Anticoagulation should not be used to extend survival of patients with end-stage cancer in the absence of other indications.

• Patients with cancer should be periodically assessed for VTE risk.

• Oncology professionals should educate patients about signs and symptoms of VTE.

Sources

• –J Clin Oncol. 2015;33:654-656.

• –J Clin Oncol. 2013;31:2189-2204.

Comments

1. VTE is the second leading cause of death among cancer patients. The highest risk cancers related to VTE are stomach and pancreas (15%). Significant risk is also associated with lung cancer, lymphoma, gynecological cancer, bladder, and testis cancer (6%).

2. Prostate and breast cancer have a significantly lower risk of VTE (0.8%–2%). Other risk factors include platelet count greater than 350,000, use of red cell growth factors, white blood cell count greater than 12,000, and BMI 35 kg/m² or higher. Inferior vena cava (IVC) filters should only be used when there is documented DVT but a contraindication to anticoagulation active bleed, melanoma, renal cell cancer or choriocarcinoma with untreated brain metastasis, platelets below 30,000 or severe platelet dysfunction. The IVC filter must be removed as soon as anticoagulation is begun. The new direct oral anticoagulants are in trials, but thus far have not been approved for patients with cancer and VTE.

3. It has been shown that in patients who present with unprovoked VTE, routine evaluation will discover 3%–5% of patients who have an underlying malignancy. A more extended workup will find additional cancers, but this has not been shown to decrease the risk of dying from the underlying cancer. Therefore, extensive evaluation is not indicated.

4. Chemotherapy (1.8-fold risk) and tamoxifen (5.5-fold risk) also predispose to VTE and these patients should be followed closely. In patients who develop clot in a vein with an indwelling venous catheter are initially managed with anticoagulation with the catheter in place. If there is pain, edema, or progression of the clot, the catheter must be removed.

Sources

• –Ann Oncol. 2011;22(suppl 6):v85-v92.

• –Blood. 2013;122:2310-2317.

• –J Thromb Thrombolysis. 2016;41:81-91

• –NCCN guidelines on cancer associated venous thromboembolic disease. 2014.

Population

• –Adults and children.

Recommendation

American Association of Blood Banks (AABB) 2014, NICE 2015, British Journal of Haematology 2016

• –Practical Considerations

  • Consider platelet transfusion based on World Health Organization (WHO) bleeding score (Table II): prophylaxis for Grade 0 or 1 and therapeutic transfusion of > Grade 2.

  • Prophylactic platelet transfusions:

    • Transfuse a single apheresis unit or a pool of 4 to 6 whole-blood-derived platelet concentrates.

    • Therapy-induced platelet counts of <10,000 (<20,000 in case of infection).

    • Elective central venous catheter (CVC): platelet count <20,000.

    • Lumbar puncture: platelet count <40,000.

    • Major nonneurological surgery or percutaneous liver biopsy with <50,000 platelets.

    • Neurosurgery or ophthalmic surgery with <100,000 platelets.

  • Not recommended:

    • Nonthrombocytopenic patients having cardiopulmonary bypass surgery unless they have perioperative bleeding with thrombocytopenia or evidence of platelet dysfunction.

    • Peripherally inserted central catheter (PICC), bone marrow aspirate, removal of central venous catheters, or cataract surgery.

    • Chronic bone marrow failure (ie, chemotherapy, bone marrow transplant).

  • Intracranial hemorrhage (traumatic or spontaneous): no evidence-based recommendations.

Sources

• –Ann Intern Med. 2015;162:205-213.

• –Blood. 2014;123:1146-1151.

• –Estcort L, et al. Guidelines for the use of platelet transfusions. Br J Haemat. 2016;176:3.

• –Stanworth SJ, Walsh TS, Prescott RJ, Lee RJ, Watson DM, Wyncoll DL. Thrombocytopenia and platelet transfusion in UK critical care: a multicenter observational study. Transfusion. 2013;53:1050–1058.

• –NICE. 2015. https://guidelines.gov/summaries/summary/49905

Comments

• Clinical Correlation

  1. These guidelines do not pertain to ITP, TTP, or heparin-induced thrombocytopenia. Platelet transfusion may worsen these immune-mediated diseases and should not be given unless there is major life-threatening bleeding. (Blood. 2015;125:1470)

  2. Consider Factor VIIa for Glanzmann thrombasthenia and transexamic acid + desmopressing in other platelet function disorders.

  3. No strong evidence was found for platelet transfusion with intracranial bleed in patients taking antiplatelet drugs or in patients undergoing neurosurgery with platelets <100,000, although platelets >100,000 is current clinical practice.

  4. Guidelines emphasize that clinical judgment and not a specific platelet count should be paramount in decision making.

  5. Beware that the risk of bacterial infection with platelet transfusion is 1 in 3000 (5 times more common than RBC transfusions). (Transfusion. 2013;55:1603)

Population

• –General population, male and female.

Recommendation

American Association of Blood Banks (AABB), 2016; NICE 2015

Comments

• Important Information

  1. Transfusion carries significant risk of infection, immunosuppression, hemolytic transfusion reaction, transfusion-related acute lung injury (TRALI) (see Table IV).

  2. Nineteen trials were evaluated by AABB assessing noninferiority of restrictive vs. liberal transfusion policy. There was no statistically significant difference, although a trend for lower mortality in the patients treated by the restrictive transfusion policy was noted.

  3. Patients with pharmacologically treatable anemia such as iron deficiency or B₁₂ or folate deficiency should not be transfused unless they are significantly symptomatic.

  4. Transfusion of red cells should be given slowly over first 15 min and completed within 4 h.

  5. In the absence of acute hemorrhage, RBC transfusions should be given as single units.

Recommendations

AABB

• –Prevention of TA-GVHD^a—High risk

  • High-risk situations include product donated by family member or HLA-selected donor.

  • Acute leukemia and Hodgkin and non-Hodgkin lymphoma patients on therapy.

  • Allogenic or autologous hemopoietic progenitor cell transplant recipient.

  • Aplastic anemia patients on antithymocyte globulin and/or cyclosporine.

  • Purine analogues and other drugs affecting T-cell count and function—fludarabine, clofarabine, bendamustine, nelarabine, alemtuzumab, and temozolomide.

  • Recommended preventive strategy is 2500 cGy of radiation to product to be transfused. This dose will destroy T cells. Shelf life of irradiated product is 28 d.

  • Infection complications of transfusion are now very rare (see Table V).

Sources

• –Ann Intern Med. 2012;157:49-58.

• –Blood. 2012;119:1757-1767.

• –Crit Care Med. 2009:37(12):3124-3157.

• –JAMA 2016;316:1984.

• –N Engl J Med. 2011;365:2433-2462.

Comments

1. Caution in the immunosuppressed:

   1. Must be aware of circumstances that increase risk of TA-GVHD in order to initiate protective strategy. If TA-GVHD does occur, mortality approaches 100%.

   2. In immunosuppressed patients and in donating family members with shared genes, targeting T cells from the donor may not be eliminated through immunologic attack. These surviving T cells then interact with host cellular antigens damaging skin, liver, GI tract, and lung with high mortality.

   3. Transfusion-related infection complications are rare with polymerase chain reaction (PCR) and antibody screening. Bacterial infection and sepsis occurs 5-fold more commonly with platelet transfusion vs. red blood cell transfusion.

   4. Immune-compromised patients needing transfusion should have CMV serology checked and if antibodies not present CMV-negative blood should be given (70%–80% of recipients are antibody positive).

Population

• –Adults.

Recommendations

ACCP 2012, ASH 2016

• –Diagnosis and Therapy

  • Diagnosis: Maintain high suspicion. If no prior heparin in the last 90 d, monitor platelet count in patients receiving heparin every 2 d from days 4–14. If previous exposure to heparin within 90 d, monitor from day 1. If platelets drop 30%–50%, suspect HIT and use 4Ts scoring model (see Table VI) to assess likelihood of HIT. If intermediate-to-high probability, treat for HIT and send immunologic (enzyme-linked immunosorbent assay [ELISA]) and functional testing (platelet serotonin release assay).

  • Treatment: (N Engl J Med. 2013;368:737-744)

    • Stop all sources of heparin.

    • Give vitamin K if the patient is on warfarin to restore proteins C and S.

    • Begin a direct thrombin inhibitor (argatroban or danaparoid). Fondaparinux is also a safe and effective alternative.

    • Avoid platelet transfusion unless life-threatening bleeding.

    • DO NOT start warfarin until platelet count is >150,000 and overlap with argatroban is for at least 5 d with the INR therapeutic for the last 2 d.

    • If no clot, then anticoagulate for 4–8 wk. If clot present, continue anticoagulation for a minimum of 3 mo.

  • Special cases:

    • Renal insufficiency: argatroban.

    • Liver dysfunction: fondaparinux and danaparoid are preferred.

    • Acute HIT with antibody-positive: bivalirudin or argatroban if urgent cardiac surgery is needed, but it is preferable to delay surgery if possible.

    • Cardiovascular surgery: if HIT occurred >100 d prior, test for antibodies. If not detected, heparin challenge can be trialed.

  • History of HIT with acute thrombosis with negative heparin antibodies should be treated with fondaparinux at full therapeutic dose until transition to warfarin. (Blood. 2012;119:2209-2218) (Annu Rev Med. 2010;61:77-90)

  • A direct oral anticoagulant (DOAC) can be substituted for warfarin to complete the course of anticoagulation.

Source

• –J Am Coll Cardiol. 2016;67:2519-2532.

Comments

• Clinical Input

  1. Highest risk for HIT is in postsurgical patients treated with UFH, with a prevalence of 0.1%–5%, with 35%–50% developing thrombosis.

  2. UFH is 8- to 10-fold more likely to cause HIT compared to LMWH. Low-molecular-weight heparin is equal if not better than UFH. UFH should be used only in patients with significant renal insufficiency.

  3. Fondaparinux (Arixtra®)—Synthetic pentasaccharide inhibiting factor X activity and is safe to be used in HIT, although direct thrombin inhibitors have previously been the anticoagulants of choice.

  4. Platelet counts can mildly decrease in the first 4 d after starting heparin but this is not immunologically mediated and is not associated with thrombosis. (Blood. 2016;128:348)

  5. HIT is an immune-mediated disorder triggered by the formation of antibodies to a heparin/platelet factor 4 antigen complex. The complex binds to platelet FC receptors, causing activation of the platelet microparticle release and increased risk of clotting.

  6. Both VTE and arterial clotting occur in the HIT syndrome in a ratio of 3:1. Adrenal infarction with shock from arterial thrombosis has been reported.

  7. HIT occurs very rarely in patients <40-y-old. HIT increases 2.4-fold in females compared to males.

  8. The median platelet count in HIT is 60,000 and seldom falls below 20,000. HIT-associated thrombosis shows a propensity to occur in areas of vessel injury (sites of central venous catheter, arterial line insertion, or other vascular interventions).

  9. The development of HIT is not related to the degree of exposure to heparin. A single flush of an IV line or 1 dose of prophylactic heparin can trigger the HIT syndrome. If HIT is not recognized, further administration of heparin will lead to significant increased risk of clot, morbidity, and mortality. (N Engl J Med. 2006;355:809-817) (JAMA. 2004;164:361-369)

  10. The 4T scoring system is most accurate in the low-risk subset, with a negative predictive value of 0.998. (Blood. 2012;120:4160-4167) (See Table VI)

Population

• –Acquired TTP in adults and children.

Recommendations

British Committee for Standards in Haematology (Br J Haematol. 2012;150:323)

• –Approach to Diagnosis and Therapy

  • Symptoms: bleeding with neurological symptoms (headache to confusion to cerebrovascular attack to coma).

  • Diagnosis is made on clinical history, laboratory tests (platelets <30,000), and review of the peripheral blood smear. Diagnosis is suspected if there is evidence of Coombs-negative microangiopathic hemolytic anemia (MAHA), elevated lactate dehydrogenase (LDH), and thrombocytopenia.

  • TTP is a medical emergency: 3 units of fresh-frozen plasma should be given while a large-bore catheter is placed for plasma exchange, which should begin within 4–8 h of presentation.

  • Order ADAMTS-13 (von Willebrand factor [vWF] cleaving enzyme) is low in >90% of patients with TTP, but treatment should be started as rapidly as possible and not wait for test results to return.

  • Lab tests:

    • CBC, reticulocyte count, haptoglobin, fibrinogen, CMP, LDH, urinalysis, Coombs, blood type, TSH, HIV, hepatitis A/B/C viruses, and autoantibodies (ANA/RF/LA/ACLA).

    • Young women should have a pregnancy test.

    • Consider EKG or echocardiogram and brain imaging (CT or MRI).

    • If diarrhea, consider stool culture for E. coli.

  • Plasma exchange (TPE) should be started with 40 mL/kg body weight plasma volume (PV) exchanges. The volume of exchange can be reduced to 30 mL/kg body weight as clinical conditions and lab studies improve.

  • Intensification in frequency of TPE to twice a day should be considered if platelet count is not rising and LDH remains high. (Transfusion. 2008;48:349)

  • Daily TPE should continue for a minimum of 2 d after platelet count >150,000 and then stopped.

  • Steroids (usually 1 mg/kg of prednisone equivalent) often administered, although benefits are uncertain.

  • In patients with neurologic and/or cardiac pathology (associated with increased mortality), rituximab should be used at a dose of 375 mg/m² weekly for 4 doses. (Blood. 2011;118:1746) (N Engl J Med. 2014;370:847)

  • Consider cyclosporin or tacrolimus in patients with acute and chronic relapsing TTP.

  • Aspirin benefit in TTP is uncertain, but it is safe at a dose of 81 mg/d with a platelet count >50,000. In patients who relapse, 20%–25% repeat the plasma exchange protocol and add rituximab weekly. The majority of relapses occur in first 30 d after remission.

  • TPE should be restarted if platelets <50,000 with the addition of rituximab. If ADAMTS-13 level drops to <5% without a drop in platelets, rituximab alone should be considered. (Blood. 2010;116:4060)

• –Supportive Therapy

  • Red-cell transfusion as clinically indicated.

  • Folate supplementation during active hemolysis.

  • Platelet transfusions are CONTRAINDICATED in TTP unless life-threatening hemorrhage (brain or GI tract).

  • Thromboprophylaxis with LMWH once platelet count >50,000.

  • Caplacizumab is a monoclonal antibody to VWD protein interfering with platelet binding and improves course of TTP. (N Engl J Med. 2016;374:511)

Sources

• –Sem Throm Haemot. 2006;32:81.

• –Blood. 2015;125:3860.

• –N Engl J Med. 354:1927.

• –Br J Haematol. 2008;142:819.

• –Transfusion. 2010;50:868.

• –Br J Haematol. 2011;153:277.

• –Br J Haematol. 2011;158(3).

Comments

• Clinical Insight

  1. Pentad: microangiopathic hemolytic anemia (MAHA), thrombocytopenia, fever, CNS symptoms, hematuria—now most commonly MAHA and thrombocytopenia only at diagnosis. Time is critical to outcome. Expedited treatment is associated with better survival.

  2. Mechanism: autoimmune disease with IgG antibody to ADAMTS-13 which prevents cleavage of large high-molecular-weight vWF. vWF binds to platelet receptor GPIB and the resulting complex obstructs the microvasculature leading to red cell fragmentation, thrombocytopenia, and organ ischemia.

  3. Plasma exchange is not a curative therapy, but protects the patient until antibody levels decline either spontaneously or with use of corticosteroids and rituximab.

  4. Mortality prior to intervention of plasma exchange in the early 1980s was 85%–90%; today the mortality is 10%–15%.

  5. Prognosis: Wyllie index of adverse features including age >40 y, hemoglobin <9.0, and fever >100.5°F (38°C) at time of diagnosis. Predictions based on 0,1, 2, or 3 of these features resulted in mortality at 6 mo of 12.5%, 14.0%, 31.3%, and 61%, respectively. (Br J Haematol. 2005;132:204)

  6. Precipitating factors: drugs (quinine, ticlopidine, clopidogrel, simvastatin, trimethoprim, and interferon), HIV infection, and pregnancy (usually in the second trimester). Removal of the fetus has not been shown to affect the course of TTP in pregnancy.

  7. Congenital TTP is rare, with <200 patients described worldwide. Onset usually is in later infancy or childhood. Patients may present as adults, with pregnancy as a common precipitant. Diagnosis is made by ADAMTS-13 activity <5%, with absence of antibody and confirmation of mutations in ADAMTS-13 gene. Treatment is with fresh-frozen plasma administration prophylactically every 10–20 d.

  8. Relapse at a rate of 20%–30%, commonly in the first month following successful therapy. Studies show monitoring ADAMTS-13 levels and instituting rituximab proactively can decrease the rate of disease relapse. (Br J Haematol 2007;136-145) (Blood. 2011;118:1746)

  9. Hemolytic uremic syndrome (HUS) clinically resembles TTP, but has a different pathophysiology, and TPE is of minimal benefit. This illness is commonly caused by bacterial toxins (Shiga-like toxin from E. coli) or drugs (quinine, gemcitabine, mitomycin C). It is also associated with malignancy and autoimmune disease. In HUS, there is disruption of the endothelium and release of high-molecular-weight vWF that overwhelms the cleaving capacity of ADAMTS-13. An antibody to ADAMTS-13 is not involved. Renal failure dominates the clinical picture and 15%–20% succumb to the disease. (Br J Haematol. 2010;148:37) (N Engl J Med. 2014;371:654)

Population

• –Adults.

Recommendations

American Society of Hematology (ASH)—Evidence-Based Practice Guidelines for ITP 2011

Diagnosis

• –Diagnosis of exclusion:

  • No reliable diagnostic test (including antiplatelet antibody studies).

  • Bone marrow examination not necessary.

  • Testing for hepatitis C and HIV.

  • Testing for another underlying illness (rheumatologic disorders, lymphoproliferative disease, H. pylori infection, antiphospholipid syndrome) is based on history and physical exam.

• –Risk factors:

  • Drug induced (trimethoprim-sulfa, rifampin, carbamazepine, vancomycin, quinine derivatives, and many more).

  • Systemic lupus/Sjögren syndrome, and other rheumatologic diseases.

  • Infections—hepatitis C, HIV, cytomegalovirus (CMV), H. pylori, Epstein–Barr virus (EBV), varicella.

  • Indolent lymphomas, breast and colon cancer.

  • Vaccinations—mostly in children.

  • Common variable immunodeficiency—almost exclusively in children.

Treatment

• –Newly diagnosed ITP:

  • Treat if platelet count <30,000 with or without bleeding.

  • Corticosteroids (prednisone 0.5–2 mg/kg daily with taper): longer course is preferred over shorter courses of high-dose corticosteroids (40 mg of decadron daily for 4 days) or intravenous immune globulin (IVIG).

  • IVIG should be used with corticosteroids when a more rapid rise in platelet count is needed, ie, surgery.

  • If platelets <30,000, second-line therapy: Rituxan is required.

  • If corticosteroids are contraindicated: IVIG or anti-D immune globulin (in patients that are Rh(+) and spleen in place). IVIG dose: 1 g/kg as a one-time dose that may be repeated as necessary. (Lancet Haematol. 2016;3:e489) (Blood. 2016;127:296) (see Table VII)

• –Unresponsive or relapse after initial therapy:

  • Splenectomy, either laparoscopic or open, should be done at least 2–4 wk after vaccination with pneumococcal, meningococcal, and Haemophilus influenzae b vaccine. Splenectomy is significantly more effective in patients less than 40-y-old compared to the elderly.

  • Thrombopoietin receptor agonists (romiplostim or eltrombopag) are often used in second-line therapy after steroids and IVIG failure or after splenectomy relapse to maintain an adequate platelet count. (Blood. 2012;120:960) (J Thromb Haemost. 2015;13:457) (Lancet. 2008;371:395) (Blood. 2013;121:537)

  • Thrombopoietin receptor agonists can be used in patients at risk for bleeding who have failed one line of therapy but have not had a splenectomy. Response rate is 80%–90%. Rituximab may be considered in patients at risk of bleeding who have failed one line of therapy, including splenectomy. (N Engl J Med. 2011;366:734) (Blood. 2014;124:3228)​​​​​

• –Treatment of ITP after splenectomy:

  • Platelets >30,000, no further treatment indicated in asymptomatic patients.

  • Platelets <30,000, second-line therapy (Rituxan, thrombopoietin receptor agonists, and immunosuppression) should be used (see Table VIII).

• –Treatment of ITP in pregnancy:

  • Corticosteroids or IVIG should be used.

  • Romiplostim and eltrombopag are not approved for use in pregnant women.

  • Refractory patients: splenectomy can be performed during second trimester.

  • Method of delivery: based upon obstetrical indications, ie, no indication for cesarean section.

• –Treatment of specific forms of secondary ITP (see Table VIII):

  • HCV-associated: Antiviral therapy should be considered in absence of contraindications. Initial therapy in this setting should be IVIG.

  • HIV-associated: start HAART first unless patient has significant bleeding complications. If ITP therapy is required use corticosteroids, IVIG, anti-D immune globulin, and romiplostim or eltrombopag. Refractory patients should have a splenectomy.

  • H. pylori-associated: Eradication therapy of newly diagnosed active H. pylori infection (stool antigen, urea breath test, endoscopic biopsy) will result in resolution of ITP in 25%–35% of patients.

Sources

• –Blood. 2016;128:1547.

• –Blood. 2011;117:4190-4207.

• –Blood. 2010;115:168-186.

Comments

• Clinical Information

  1. Be aware of autosomal-dominant hereditary macrothrombocytopenia. Platelets are large, hypogranular, and misshapen with counts between 30 and 60,000. Bleeding is modest but is often confused with ITP. The treatment is with platelet transfusion for significant bleeding. Treatment for ITP is ineffective.

  2. TTP (thrombotic thrombocytopenic purpura) should always be excluded. Symptoms: ill, low-grade fever, myalgia, chest pain, and altered mental status. Labs: thrombocytopenia and a hemolytic anemia with red cell fragmentation, elevated reticulocyte count, and significant elevation of lactate dehydrogenase. This is a medical emergency and should be treated urgently with plasma exchange.

  3. In the elderly, myelodysplastic syndrome is common, but isolated thrombocytopenia occurs in <10%. ITP is by far the most common cause of isolated thrombocytopenia, even in elderly patients.

  4. Treating patients for active H. pylori infection with new-onset ITP will result in a durable complete remission in up to 50% of patients.

  5. Be alert to pseudothrombocytopenia caused by platelet clumping in response to ethylenediaminetetraacetic acid (EDTA). Reviewing the peripheral smear or repeating the platelet count in a citrated or heparinized tube is needed to make the diagnosis.

  6. Platelet transfusion should be considered along with standard therapy when there is life-threatening hemorrhage (usually brain or GI tract). The platelet count usually will not rise significantly, but bleeding can be slowed. Do not give prophylactic platelets based on platelet counts <5000 or for minor bleeding.

  7. Anti-D immune globulin therapy (WinRho) is associated with a small percentage of patients developing disseminated intravascular coagulation (DIC) and resultant death. Close monitoring of patients is required. This therapeutic approach is used much less frequently because of complications and more effective new drugs.

Population

• –Pediatric.

Recommendations

American Society of Hematology (ASH)—Evidence-Based Practice Guidelines for ITP 2011

• –Diagnosis:

  • Bone marrow (BM) examination unnecessary in children and adolescents with typical features of ITP (isolated thrombocytopenia, large, morphologically normal platelets, asymptomatic except for bleeding).

  • BM also not necessary in patients failing intravenous IVIG therapy or before splenectomy.

• –Initial management:

  • Absent or mild bleeding (bruising, petechiae): observation alone regardless of platelet count.

  • Moderate-to-severe bleeding: single dose of IVIG (0.8–1 g/kg) or short-course corticosteroid is first line.

  • Anti-D immune globulin (WinRho): first-line therapy in Rh-positive, nonsplenectomized children needing treatment.

• –Second-line treatment for pediatric ITP:

  • Rituximab can be considered if bleeding ongoing despite IVIG, anti-D immune globulin, and steroids. Rituximab can be considered an alternative to splenectomy or in patients not responding to splenectomy.

  • High-dose dexamethasone (0.6/kg/d × 4 d q 4 wk) may be considered for patients with bleeding and persistent thrombocytopenia despite appropriate therapy.

• –Splenectomy: (Blood. 2013;121:4457-4462) (Blood. 2010;115:168-186) (Pediatr Blood Cancer. 2009;53:652-654) (Blood. 2014;124:3295)

  • Chronic ITP who have significant or persistent bleeding and lack of responsiveness or intolerance to other standard therapies.

  • Do not do splenectomy for at least 12 mo after start of ITP treatment unless severe disease with significant serious bleeding risks.

  • Splenectomy in patients over 45 y has a significant risk of recurrence of thrombocytopenia compared to splenectomy in patients younger than 45 y.

Sources

• –Pediatr Blood Cancer. 2009;53:652-654.

• –Blood. 2010;115:168-186.

• –Blood. 2013;121:4457-4462.

• –Blood. 2014;124:3295.

Comments

1. Measurement of immunoglobulin to exclude common variable immune deficiency (CVID) is common practice as ITP can be the presenting feature of CVID.

2. In a study of 332 children with typical ITP with bone marrow biopsy, no leukemia, only 1 child was found with BM aplasia.

3. Treatment focuses on severity of bleeding, not platelet cell count. In a study of 505 children with platelets <20,000 and skin bleeding, only 3 patients developed severe bleeding and none had intracranial hemorrhage.

4. The older the child or adolescent, the more likely they are to have chronic ITP (defined as platelet count <150,000 at 6-mo follow-up). Rate for children age 3–12 mo = 23%; children >12 mo and <10 y = 28%; and children >10 y = 47%.

5. Anti-D immune globulin therapy more effective at 75 vs. 50 μg/kg, but increased toxicity including small percentage with DIC. Drop in hemoglobin averages 1.6 g/dL.

6. Response rate to splenectomy is 70%–80%, but unless a child has severe unresponsive disease, delay the splenectomy for at least 12 mo since 20%–30% will have spontaneous remission.

7. Immunized patients undergoing splenectomy at least 2 wk before surgery with pneumococcal, meningococcal, and H. influenzae type b vaccine.

8. Rituximab efficacy varies from 30% to 50% in trials. Serious side effects: serum sickness, severe hepatitis in hepatitis B carriers, and rare cases of multifocal leukoencephalopathy.

9. MMR (measles, mumps, rubella) vaccination-induced ITP occurs in 2.6 per 100,000 vaccine doses. ITP following natural measles or rubella infection ranges from 600 to 1200 per 100,000 cases, justifying the overall clinical benefit of the vaccine.

10. Thrombopoietin receptor agonists (romiplostim and eltrombopag) are active agents for ITP in adults but have not been adequately studied in children. Ongoing studies show benefit but not yet approved by FDA.

Population

• –Adults and children over 1 y.

Recommendation

NICE 2015

• –Alternatives to blood transfusion

  • Do not recommend erythropoietin therapy for surgical patients unless patient has anemia and meets the criteria for blood transfusion, but declines it because of religious beliefs.

  • Iron therapy is recommended for all patients before and after surgery to patients with iron-deficiency anemia.

    • Oral iron therapy is standard.

    • Intravenous iron can be considered for patients:

      1. Cannot tolerate oral iron.

      2. Cannot absorb oral iron.

      3. Time interval before surgery is too short for oral iron to be effective.

  • Offer tranexamic acid (TXA) for people undergoing surgery with expected blood loss >500 mL or >10% blood volume.

  • Offer cell salvage with TXA for patients undergoing surgery with expected high volume of blood loss.

Sources

• –Crookston K. The approach to the patient who declines blood transfusion. 2018. www.uptodate.com.

• –https://guidelines.gov/summaries/summary/49905

Comments

1. Correct coagulopathy, enhance hemostasis, and replete vitamin deficiencies, ie, Vitamin K, prothrombin complex concentrations, transexamic acid, B₁₂, folate, iron.

2. Supplemental oxygen can be supplied.

3. Consider autologous blood donation in advance of surgery, although have marginal clinical and cost effectiveness.

4. Consider cell salvage therapy for cardiac surgery, complex vascular surgery, major obstetrical procedures, and pelvic reconstruction or scoliosis surgery.

5. Topical medications can be applied intraoperatively, such as collagen gel, cellulose, and thrombin.

6. Have a discussion with the patient and surgeon about techniques to limit blood loss, ie, hemostasis, hypotensive anesthesia, intraoperative hemodilution, blood salvage, and hypothermia.

7. Limit blood draws and use pediatric-sized blood draw tubes.

Population

• –Adults and children over 1 y.

Recommendations

NICE 2015

• –Recommends cryoprecipitate for patients with significant bleeding and fibrinogen level <150 mg/dL.

• –Consider cryoprecipitate for patients who require an invasive procedure or surgery with high risk of bleeding and fibrinogen level <100 mg/dL.

Source

• –https://guidelines.gov/summaries/summary/49905

Population

• –Adults and children over 1 y.

Recommendations

NICE 2015

• –Consider FFP transfusion for patients with active bleeding and prothrombin time or activated partial thromboplastin time ratios above 1.5.

• –Do not recommend FFP transfusions for patients with an abnormal coagulation profile who are not actively bleeding.

Source

• –https://guidelines.gov/summaries/summary/49905

Comment

1. Typical dose of FFP is 15 mL/kg.

Population

• –Adults and children over 1 y.

Recommendation

NICE 2015

• –Recommend for emergency reversal of Coumadin anticoagulation in patients with:

  • Severe bleeding.

  • Suspected intracranial hemorrhage.

Source

• –https://guidelines.gov/summaries/summary/49905

Population

• –Patients with DVT (lower and upper extremity).

Recommendations

ACCP 2016, ACP 2012

• –For diagnostic workup of DVT/PE, see Figures I–III.

• –Treatment variables

  • Initial heparin-based regimen with unfractionated heparin (UFH) 80 U/kg bolus, then 18 U/kg/h titrated to partial thromboplastin time (PTT), enoxaparin 1 mg/kg SQ q12h or 1.5 mg/kg SQ daily.

  • Fondaparinux 5 mg (<50 kg), 7.5 mg (50–100 kg), or 10 mg (>100 kg) SQ daily.

  • Start warfarin (≤10 mg) on day 1 and overlap with heparin for at least 5 d with therapeutic INR for last 2 d. Rivaroxaban, dabigatran, apixaban, and edoxaban are all now approved by FDA to treat acute DVT and PE history (DOACs—direct oral anticoagulants)—see Table IX. Extended treatment has shown protection from further clot with minimal bleeding risk. Rivaroxaban is now approved in acute coronary syndrome. (N Engl J Med. 2010;363:2499-2510) (N Engl J Med. 2012;366:1287-1297) (Am J Coll Cardiol. 2013;62:286) In setting of unprovoked DVT or PE, men have a 50% increased risk of recurrent clot compared to women. (Medicine. 2014;93:309)

  • Outpatient management of VTE with rivaroxaban, apixaban, edoxaban, or dabigatran is acceptable if the patient does not have any of the following: >80-y-old, history of cancer, hx of COPD, CHF, pulse >110, BP <100, O₂ sat <90.

  • Knee-high GCS (graduated compression stockings) with 30–40 mm Hg pressure at ankles for 2 y will reduce post-thrombotic syndrome risk by 50%.

Source

• –Chest. 2016;149:315-352.

Comments

1. Clinical findings alone are poor predictors of DVT.

2. Early ambulation on heparin is safe.

3. With iliofemoral thrombosis and significant swelling, thrombolysis or surgical thrombectomy not recommended unless significant symptoms.

4. Inferior vena cava (IVC) filter indicated if DVT and significant uncontrolled bleeding precluding anticoagulation. (Chest. 2016;150:1182)

5. With provoked clot, anticoagulate for 3 mo if precipitating problem is solved.^a

6. Continue anticoagulation indefinitely if provoking problem continues.

7. In cancer-related clots, continue low-molecular-weight heparin (LMWH), do not transition to warfarin if cancer still active. (Blood. 2014;123:3972)

8. In unprovoked clot, anticoagulate for 3 mo then weigh risk of bleeding to benefit of prolonged anticoagulation to prevent clot; consider thrombophilia evaluation, including hereditary factors and antiphospholipid antibody syndrome. Men have a 50% increase in recurrent clot compared to women, and if first clot is a PE, indefinite anticoagulation is advised because of high risk of the next event being a PE (60% vs. 20%) compared to those with VTE only.

9. Rivaroxaban and other DOACs should not be used in pregnancy or in patients with liver disease.

10. Risk factors for warfarin bleeding—age >65 y, history of stroke, history of GI bleed, and recent comorbidity (MI, Hct <30, creatinine >1.5, diabetes). If all 4 factors present, 40% risk of significant bleed in 12 mo; 0.4% of patients on warfarin die of bleeding yearly. (Chest. 2016;149:315) (Am J Med. 2011;124:111)

11. Patients with mild symptoms and good support system can be treated as outpatient with rivaroxaban (direct factor Xa inhibitor), other DOACs, or with lovenox and warfarin.

12. Calf and iliofemoral thrombosis have increased incidence of false-negative compression ultrasound—recommend CT or MR venogram or venography for suspected iliofemoral thrombosis, and for calf thrombosis follow-up compression ultrasound (CUS) in 5–7 d is acceptable.

13. Normal D-dimer with abnormal CUS in leg with previous DVT makes new clot unlikely. (J Thromb Haemost. 2007;5:1076)

14. Consider high thrombophilic risk in patients with recurrent VTE or patients with first unprovoked VTE who have the following characteristics:

    • Age <50-y-old.

    • Family history of VTE.

    • Unusual site of thrombosis.

    • Massive venous thrombosis.

15. In unprovoked VTE 3% of patients are found to have associated malignancy with another 10% diagnosed with cancer over the next 2 y. (N Engl J Med. 1998;338:1169) (Ann Intern Med. 2008;149:323) (N Engl J Med. 2015; 373:697)

16. In patients with the antiphospholipid antibody syndrome and a new venous thrombosis, transition to warfarin is superior to using the new oral anti-coagulants. (Am J Hematol. 2014;89:1017)

Population

• –Diagnosed pulmonary embolism.

Recommendations

ACCP 2016, ACP 2011

• –Approach to initial anticoagulation is the same as DVT.

• –If patient is hypotensive without high bleeding risk and tachycardiac, systemically administered thrombolytic therapy is recommended.

• –In a patient with acute PE associated with hypotension with contraindications to or failed thrombolysis or in shock that is likely to lead to rapid death, catheter-assisted thrombus removal is indicated if appropriate expertise and resources are available.

• –In patients whose first episode of VTE is an unprovoked PE, extended anticoagulation beyond 3 mo is preferred unless high risk of bleeding.

Source

• –Chest. 2016;149:315-352.

Comments

• Clinical Observations

  1. Patients whose first VTE is a PE will have a 3-fold increased risk of a second clot being a PE compared to patients with DVT only. (N Engl J Med. 2010;363:266)

  2. In patients with unprovoked PE or DVT elevated D-dimer at the time of discontinuation of warfarin or 2–3 wk after stopping anticoagulants predicts for a 3- to 5-fold increase in risk of clot over the next 12 mo. (Blood. 2010;115:481)

  3. The presence of a permanent IVC filter does not mandate continuous anticoagulation unless documented recurrent clot problems.

  4. Unprovoked clot has risk of recurrent clot in first 12 mo of 8%–12% vs. 3% for patients with provoked clot. (JAMA. 2011;305:1336)

  5. Patients with intermediate or high pretest probability (PTP) of PE should be treated with heparin before diagnostic workup is complete.

  6. Asymptomatic PE (found incidentally on chest CT) should be treated with same protocol as symptomatic PE. (Blood. 2015; 125:1877)

  7. Emerging data suggest the use of aspirin (100 mg PO daily) may reduce the risk of recurrent clot in patients with unprovoked VTE after 6 to 12 mo of warfarin therapy. (N Engl J Med. 2012;366:1959)

  8. Patients with significant risk of recurrent clot, on long-term anticoagulation with reduced dose of a DOAC, have continued protection from clot and reduced risk of bleeding (rivaroxiban—10 mg/d, apixaban 2.5 mg bid). (N Engl J Med. 2017;376:1279,1211)