Bleeding Disorders

Educational Objectives

The goal of this program is to improve management of bleeding disorders. After hearing and assimilating this program, the clinician will be better able to:

1. Optimize the management approach for a patient with excessive bleeding.
2. Use bleeding assessment tools to assess excessive bleeding.
3. Evaluate patients for hemophilia.

Summary

Bleeding disorders: primary hemostasis disorders — include platelet disorders, eg, quantitative defect from thrombocytopenia, qualitative defect in a membrane tissue, secretion defect, and von Willebrand disease (VWD), and connective tissue disorders, eg, Ehlers-Danlos syndrome or collagen fibril defects; secondary hemostasis disorders — include hemophilia, rare autosomal recessive disorders, and acquired disorders (patients with comorbidities, liver disease, disseminated intravascular coagulation [DIC], or anticoagulants); other types — include inherited fibrinolysis (rare) and acquired fibrinolysis; hyperfibrinolytic disorders, excess clot breakdown in DIC, prostate cancer, or liver disease are rarely seen

Evaluation: consider platelets, fibrin, their interaction, and connective tissue along with prothrombin time (PT; extrinsic factors) and partial thromboplastin time (PTT; intrinsic factors); the International Society Thrombosis and Hemostasis Bleeding Assessment Tool (BAT) has been designed and validated for primary care clinics; high scores are sensitive for adults with congenital bleeding disorders; BAT scores of <4 in adult males, <6 in adult females, and <3 in children are considered normal; additional workups and referrals to hematology are recommended if the score is above normal

Bleeding history: differentiate between congenital and acquired bleeding and determine the bleeding site; ask about the age when the bleeding started, bruising history, family history of bleeding, wisdom teeth extractions in childhood, and menstrual bleeding history; primary hemostasis disorders cause mucosal bleeding; severe factor deficiencies cause deep muscle and joint bleeding; consider intake of medicines and supplements (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], selective serotonin reuptake inhibitors [SSRIs], fish oils, herbal medicines, antiplatelet medications), skin, history of chronic obstructive pulmonary disease or autoimmune disorders, prolonged exposure to steroids, and age (for solar purpura or thinning of skin); assess patients for connective tissue disorder and benign joint hypermobility syndrome

Common Congenital Bleeding Disorders

Hemophilia A and B: most common congenital bleeding disorders; patients are at risk for deep bleeding; occurs in 1 out of 5,000 to 7,500 male births worldwide; new mutation rate is high (≤30%); can occur in all racial groups and patients without a known family history of bleeding disorders; characterized by prolonged activated PTT (low factor VIII [FVIII] and factor IX [FIX]) and normal PT; hemophilia A is a FVIII deficiency and an X-linked disorder and accounts for 80% to 90% of patients with hemophilia; an X-linked FIX deficiency occurs in 10% to 20% of patients; autosomal recessive ones are rare (<1%)

Bleeding patterns: mild — patients have an FVIII or FIX level of 5% to 40%; typically bleed after mild trauma, eg, surgeries, dental procedures; severe factor deficiency — results in spontaneous bleeding in joints and muscles, requiring health care factors and modalities; moderate — bleeding can vary; life-threatening bleeding — occurs in tight spaces, eg, the CNS, head, neck, and throat; gastrointestinal, retroperitoneal, and iliac bleeding can cause considerable blood loss

Bleeding sites: hemarthrosis or joint bleeding — common; repeated bleeding in the same joint can lead to arthritis; tingling or bubbling sensation, pain, stiffness, swelling, and impaired range of motion can occur; prompt treatment with factor is recommended; repeated episodes of hemarthrosis can lead to synovial hypertrophy, which can cause end-stage osteoarthritis; muscle bleeding — begins with vague pain and progresses to heat, swelling, inability to move the muscle, and tightness of skin; compartment syndrome is a concern; the “5 P’s” of pain, ie, pain with passive stretch, pain out of proportion, paresthesia, pallor, and pulselessness, are considered an emergency

Management: short-acting factors are considered for hospitalized patients; FVIII has a half-life of 8 to 12 hr and FIX has a half-life of 18 to 24 hr; longer acting factors are available for outpatient treatment; patients with mild bleeding are treated on demand for bleeds, while patients with severe bleeding are given factor prophylactically to prevent spontaneous bleeding; adjunctive treatments — desmopressin (DDAVP) can be used in patients with mild FVIII deficiency, VWD, and qualitative platelet defects; hyponatremia and seizure are concerns; antifibrinolytic agents, eg, aminocaproic acid (Amicar), tranexamic acid (Lysteda), are helpful adjuncts for mucosal bleeding; RICE (rest, ice, compression, and elevation) is recommended when bleeding occurs; US Food and Drug Administration (FDA)-approved gene therapies for FIX and FVIII are available; emicizumab is a recombinant FVIII product; subcutaneous injection is available (easier alternative to IV infusions); emicizumab is FDA-approved for bleeding prophylaxis in patients with FVIII deficiency

Complications: older patients with hemophilia may have acquired HIV or hepatitis C infection from receiving contaminated blood in the 1970s or 1980s; increased bleeding may occur if inhibitory antibodies form against the factor, requiring alternative therapies that bypass FVIII and FIX

Von Willebrand disease: most common bleeding disorder; 1 of 100 people with bleeding disorders have low VWF levels; people with type O blood tend to have lower VWF levels; 1% of patients are symptomatic; type 1 — a mild quantitative decrease in VWF level and function; levels can be 30% to 50%; type 2 — occurs when there is a qualitative defect; type 3 — rare, with no or markedly decreased VWF function; gene mutations — are scattered in type 1 disease (difficult to identify through mutation testing); type 2 disease affects collagen, platelet, or FVIII binding; type 3 are from large homozygous one sided deletions or double heterozygous deletions causing severe low levels; patients with type 1 are most common with mild mucosal bleeding disorder and nosebleeds, gum bleeds, excessive bruising, heavy menstrual bleeding; postpartum hemorrhage and postoperative bleeding are concerns; if patients lack VWF, patients may present similar to hemophilia with hemarthrosis

Evaluation: the coagulation laboratory offers a VWF panel including FVIII activity, VWF antigen, GP1bM activity, and collagen binding; can send for multimer analysis; testing commonly needs to be repeated; FVIII and VWF can be high if the patient is stressed or on estrogen-containing oral contraceptives

Treatment: DDAVP is typically used; infusions are given to assess patient response (even before undergoing a procedure); type 2 VWD may not respond well; if disease is severe or the response to DDAVP is poor, VWF containing factor concentrates (HUMATE-P) or other newer recombinant factor products can be given; mucosal bleeding — antifibrinolytic therapy (aminocaproic acid, tranexamic acid) is mainly used; consult with gynecology for hormonal contraception and levonorgestrel-containing intrauterine device products; tranexamic acid is the first-line treatment for heavy menstrual bleeding; intranasal DDAVP is difficult to tolerate; avoid supplements that can increase bleeding, NSAIDs, and aspirin

Qualitative platelet defects: can be caused by congenital defects or medications, eg, aspirin, dipyridamole, cilostazol; GP IIb/IIIa activation can help; presentation is similar to VWD; diagnosis is not clear; a high-power electron microscope can be used to examine the granules in platelets; the gold standard involves obtaining platelets from patients and subjecting them to different agonists ex vivo; management — similar to VWD; often involves antifibrinolytic therapy for heavy menstrual bleeding and mucosal bleeding; intranasal or IV DDAVP are used for procedures and platelet transfusions are used for large surgeries

Factor deficiencies: rare and inherited in a autosomal recessive pattern; can cause mild or severe bleeding depending on the actual level of the factor; these patients often have a family history and are identified earlier; refer patients to a hemophilia treatment center if the mixing study does not correct

Acquired bleeding disorder: assess in new onset of bleeding; check for medications that affect platelets; SSRIs can cause surface mucosal bruising; serotonin-norepinephrine reuptake inhibitors can cause more significant bruising; aspirin, clopidogrel, and NSAIDs also affect platelets; ask about supplements, eg, fish oil, turmeric, ginger, vitamin E, garlic, ginseng, and cinnamon bark; uremia, renal dysfunction, and hematologic malignancies can lead to decreased platelet hemostasis; significant surgeries, extracorporeal membrane oxygenation, or pulmonary bypass can contribute; bone marrow issues or myeloproliferative neoplasms are other causes; acquired VWD — second most common acquired bleeding disorder; presents as mucosal and less common than platelet defects; hematologic malignancies were the primary cause, but cardiologic causes, eg, aortic stenosis, are increasingly common; was a concern with left ventricular assist devices; may be associated with autoimmune disorders; management — treat the underlying disorder; consider acquired specific inhibitors of blood clotting factors because of the high mortality rate; occurs rarely (often in older patients); patients may have new-onset severe life-threatening bleeding; recombinant factor VII (NovoSeven) and activated prothrombin complex concentrate can help

Liver disease: can cause increased bleeding; all coagulation factors are made in the liver except FVIII; supportive care is recommended to maintain fibrinogen levels and platelets (if thrombocytopenia); consider concomitant vitamin K deficiency; antifibrinolytic agents can be used if the bleeding to clotting ratio is known

Disseminated intravascular coagulation: excessive activation of coagulation and fibrinolysis systems lead to consumptive coagulopathy; usually secondary to an underlying disorder; sometimes associated with acute promyelocytic leukemia, toxins, trauma, burns, snake venoms, placental abruption, or amniotic fluid embolisms in pregnant women; can be a chronic process in patients with cancer; associated with low factor levels and high PT and PTT; thrombocytopenia is associated with low D-dimer levels; management involves supportive care and treatment of the underlying disorder

Readings

Castaman G, Goodeve A, Eikenboom J. Principles of care for the diagnosis and treatment of von Willebrand disease. Haematologica. 2013;98(5):667–674. doi: 10.3324/haematol.2012.077263; Castaman G, Matino D. Hemophilia A and B: Molecular and clinical similarities and differences. Haematologica. 2019;104(9):1702–1709. doi: 10.3324/haematol.2019.221093; Du P, Bergamasco A, Moride Y, et al. Von Willebrand disease epidemiology, burden of illness and management: A systematic review. J Blood Med. 2023;14:189–208. doi: 10.2147/JBM.S389241; Elbatarny M, Mollah S, Grabell J, et al. Normal range of bleeding scores for the ISTH-BAT: Adult and pediatric data from the merging project. Haemophilia. 2014;20(6):831–835. doi: 10.1111/hae.12503; Levi M, Sivapalaratnam S. Disseminated intravascular coagulation: an update on pathogenesis and diagnosis. Expert Rev Hematol. 2018;11(8):663-672. doi:10.1080/17474086.2018.1500173; Lukes AS, Kouides PA, Moore KA. Tranexamic acid: A novel oral formulation for the treatment of heavy menstrual bleeding. Women’s Health. 2011;7(2):151-158. doi:10.2217/WHE.11.9; Tiede A, Collins P, Knoebl P, et al. International recommendations on the diagnosis and treatment of acquired hemophilia A. Haematologica.2020;105(7). https://doi.org/10.3324/haematol.2019.230771.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into from content: Dr. Sood has received research support from Pfizer. Members of the planning committee reported nothing relevant to disclose. Dr. Sood's lecture includes information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Sood was recorded at the General Anemias and Anticoagulation Management Seminar, held virtually on November 2, 2024, and presented by the University of Michigan Medical School. For information on future CME activities from this presenter, please visit medschool.umich.edu/offices/cme. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.25 CE contact hours.

Lecture ID:

FP731801

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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