evaluation of abnormal bleeding

1. Evaluation of Abnormal Bleeding Ambulatory Medicine Clerkship 01/11/2010 Kofi-Buaku Atsina YSM III

2. Learning Objectives List the differential diagnoses of abnormal bleeding in an adult. Describe the appropriate diagnostic evaluation for abnormal bleeding in an adult. Interpret coagulation assays and understand their role in refining differential diagnosis Understand the coagulation cascade Describe the physiologic role of von Willebrand factor in clotting

3. Case 1 HPI: A 62 y/o mildly overweight black woman with h/o hypertension presents with gingival bleeding after periodontal scaling of her lower-right second molar 5 hours prior to the episode. Her bleeding had persisted despite application of ice and pressure. She reports a similar episode 6 months earlier, also after a periodontal procedure, in which bleeding stopped only after the application of firm pressure for 6 hours. She is otherwise in her USOH and denies any easy bruising, epistaxis, rectal bleeding, hemturia, weakness, fatigue, lightheadedness, fever, arthralgia, dyspnea, jaundice, adbominal pain, back pain, rash or confusion.

4. PMH/PSH Deep-vein thrombosis in the legs (20 years ago) Cosmetic blepharoplasty, w/o bleeding complications (@ age 20) Arthroscopic repair of meniscal tear in the left knee without bleeding complications (1 year ago) Uncomplicated vaginal delivery SH Former smoker, quit 30 years ago Consumes alcohol infrequently FH Father died of lung cancer at age 62 Mother still living and in good health at age 88 Brother had colorectal cancer at age 57 No h/o bleeding diathesis Meds Thiazide diuretic Allergies NKDA Cosmetic blepharoplasty = cosmetic eyelid surgeryCosmetic blepharoplasty = cosmetic eyelid surgery

5. Physical Exam Gen: NAD Vitals: BP: 128/76 mm Hg, P: 80 and regular, RR: 16, O2 saturation 98% on ambient air. HEENT: Oral cavity revealed blood slowly oozing from the vicinity of the lower-right second molar, with no visible mucosal laceration. But no oral petechiae, bullae, or ulcers. Mild conjunctival pallor was noted, but no scleral icterus. There was no lymphadenopathy. RESP: Clear to auscultation and percussion. Cor: Mild lateral apical displacement; RRR, no murmur, rub, or gallop. Abd: Soft and not tender; normal bowel sounds and no hepatosplenomegaly or masses detected. Rectal examination revealed no masses and a scant amount of brown stool that was negative for occult blood. EXT: Her extremities were warm, with brisk capillary refill, and no clubbing, cyanosis, or edema. No rashes, petechiae, ecchymoses, or telangiectasias were noted. Neuro: cranial nerves intact, 5/5 muscle strength, normal sensation, 3/5 deep-tendon reflexes, normal coordination, and gait.

6. Differential diagnosis? Acquired Trauma Drugs: Aspirin, wafarin, heparin Platelet disorder: ITP, TTP/HUS, HIT Clotting factor deficiency Liver disease, malnutrition, clotting factor inhibitor, acquired von willebrand disease Combined platelet and clotting factor disorder: DIC Vessel wall disease: acquired vasculitides Genetic Platelet disorder Bernard Soulier syndrome, Glanzmann’s thrombasthenia, storage pool disorders Clotting factor deficiency Hemophilia A, Hemophilia B, von Willebrand disease Vessel wall abnormalities: Ehlers-Danlos syndrome NB. Acquired vasculitides e.g Henoch Schonlein Purpura Bernard-Soulier Syndrome - Defect of adhesion, inherited deficiency of platelet membrane glycoprotein Gp Ib-IX, needed for normal platelet adhesion to subendothelial membrane Storage Pool Disease (defect in dense bodies); Grey Platelet Syndrome (defect in alpha bodies) - Diseases of platelet activation (Dense bodies: ADP, serotonin, calcium)/(Alpha granules: PF4, BTG, PDGF, VWF, Factors V & VIII, IgG) Glanzmann’s Thrombasthenia - Defect in aggregation; inherited deficiency of platelet membrane glycoprotein Gp IIb-IIIa, needed for platelets to bind with each other via vWF and aggregate with each other. Platelet Procoagulant -- Scott SyndromeNB. Acquired vasculitides e.g Henoch Schonlein Purpura Bernard-Soulier Syndrome - Defect of adhesion, inherited deficiency of platelet membrane glycoprotein Gp Ib-IX, needed for normal platelet adhesion to subendothelial membrane Storage Pool Disease (defect in dense bodies); Grey Platelet Syndrome (defect in alpha bodies) - Diseases of platelet activation (Dense bodies: ADP, serotonin, calcium)/(Alpha granules: PF4, BTG, PDGF, VWF, Factors V & VIII, IgG) Glanzmann’s Thrombasthenia - Defect in aggregation; inherited deficiency of platelet membrane glycoprotein Gp IIb-IIIa, needed for platelets to bind with each other via vWF and aggregate with each other. Platelet Procoagulant -- Scott Syndrome

7. Acquired or Genetic? Acquired Based on history: Generally healthy person PMH/PSH Cosmetic blepharoplasty, w/o bleeding complications Arthroscopic repair of meniscal tear in the left knee without bleeding complications Uncomplicated vaginal delivery

8. Nature of Bleeding Mucosal Bleeding (petechiae, purpura), menorrhagia, prolonged bleeding from minor wounds --> Platelet disorder/ vWF disorder Deep Tissue Bleeding (Hemathrosis, hematomas, ecchymosis, prolonged post-surgical bleeding ) --> Coagulation factor defect/deficiency

9. Platelet/vWF disorder or Coagulation disorder? Acquired: Platelet Disorder Quantitative: Bone marrow diseases e.g. aplastic anemia, marrow infiltration (leukemia), drug induced e.g alcohol, thiazides, infection (HIV, measles) Infections eg. HIV, CMV, infectious mononucleosis Immunological e.g. ITP Nonimmunologic e.g.TTP/HUS Drug induced e.g. Heparin, quinidine, sulfa compounds Hypersplenism Qualitative: Aspirin/NSAID Uremia Acquired von Willebrand Disease Hypothyroidism, Mechanical/Shear stress, Lymphoproliferative diseases, Pancreatitis, DIC,Decompensated cirrhosis NB. Aspirin/NSAID: They are COX inhibitors that needed for synthesis of factors like thromboxane and prostaglandins needed in platelet aggregation. Uremia is known to cause an acquired defect in platelet function, although the mechanism is presently unknown.NB. Aspirin/NSAID: They are COX inhibitors that needed for synthesis of factors like thromboxane and prostaglandins needed in platelet aggregation. Uremia is known to cause an acquired defect in platelet function, although the mechanism is presently unknown.

10. Effectors of Hemostasis Vessel Wall Integrity vWF Platelet adhesion, activation and aggregation Coagulation Cascade Anticoagulants and fibrinolytic factors

11. vWF, Platelet Adhesions and Aggregation Primary HemostasisPrimary Hemostasis

12. Coagulation cascade Secondary hemostasis Secondary hemostasis

13. PT/PTT *Lupus anticoagulant: a medical phenomenon whereby lupus antbody binds to phospholipids and other cell surface proteins and inhibits these cells from interating with coagulation factors for proper coagulation cascade to occur. Çan lead to prolonged PT and PTT values. *Heparin can affect PTT values, *Therapeutic doses of Wafarin - Vitamin K inhibitor, Vitamin K deficiency can affect PT values because factor 7 in the extrinsic pathway is K dependent *Supratherapeutic doses of Warfarin can prolong both PT and PTT because FIX, is also K dependent*Lupus anticoagulant: a medical phenomenon whereby lupus antbody binds to phospholipids and other cell surface proteins and inhibits these cells from interating with coagulation factors for proper coagulation cascade to occur. Çan lead to prolonged PT and PTT values. *Heparin can affect PTT values, *Therapeutic doses of Wafarin - Vitamin K inhibitor, Vitamin K deficiency can affect PT values because factor 7 in the extrinsic pathway is K dependent *Supratherapeutic doses of Warfarin can prolong both PT and PTT because FIX, is also K dependent

14. Assays for Von Willebrand factor Quantitative or qualitative defects: von Willebrand Ristocetin Cofactor von Willebrand Antigen Factor VIII level Qualitative defects: Von Willebrand multimer gel analysis Ristocetin-induced platelet aggregation (RIPA) Notes: Ristocetin is an antibiotic that has the ability to induce platelet agglutination when added in the presence of vWF multimers. vWF in plasma does not bind to platelet receptor Gp Ib-IX, unless it is expose to the subendothelial connective tissue and structurally modified. Ristocetin is thought to work in a similar fashion. Thus, 1. Ristocetin cofactor measures how well vWF binds to platelets; so it’s a measure of vWF functionality 2. vW antigen assay is a quantitative measure of how much vWF is present in any given plasma sample 3. Factor VIII levels -quantitative measure of functional factor VIII because as mentioned before vWF is a carrier for FVIII and helps preserve it in the blood stream. A deficiency is FVIII could mean a deficiency in vWF; normal levels do not exclude vW disease especially for type 2 vWD. Qualitative test like: 4. the vWF multimer gel analysis helps to classify which type of vW disease is present. 5. RIPA is also a qualitative test of vWF functionality, but unlike ristocetin cofactor assay, it is able to diagnose type 2 vWF disease and Bernard Soulier syndrome (defect in gp 1b). For a test to be normal, the addition of ristocetin should cause agglutination of platelets.Notes: Ristocetin is an antibiotic that has the ability to induce platelet agglutination when added in the presence of vWF multimers. vWF in plasma does not bind to platelet receptor Gp Ib-IX, unless it is expose to the subendothelial connective tissue and structurally modified. Ristocetin is thought to work in a similar fashion. Thus, 1. Ristocetin cofactor measures how well vWF binds to platelets; so it’s a measure of vWF functionality 2. vW antigen assay is a quantitative measure of how much vWF is present in any given plasma sample 3. Factor VIII levels -quantitative measure of functional factor VIII because as mentioned before vWF is a carrier for FVIII and helps preserve it in the blood stream. A deficiency is FVIII could mean a deficiency in vWF; normal levels do not exclude vW disease especially for type 2 vWD. Qualitative test like: 4. the vWF multimer gel analysis helps to classify which type of vW disease is present. 5. RIPA is also a qualitative test of vWF functionality, but unlike ristocetin cofactor assay, it is able to diagnose type 2 vWF disease and Bernard Soulier syndrome (defect in gp 1b). For a test to be normal, the addition of ristocetin should cause agglutination of platelets.

15. Case 1: Labs

16. Labs

17. What is your refined DDx?

18. Acquired Von Willebrand disease Causes: Hypothyroidism Mechanical/Shear stress, Lymphoproliferative diseases/ collagen vascular diseases Pancreatitis, DIC, Decompensated cirrhosis Tumor 1. Hypothyroidism: A fall in production of thyroid hormones can result in a decrease in cellular metabolism and therefore lowered synthesis of von Willebrand factor 2. Mechanical/Shear Stress: They uncoil vWF multimers, exposing ADAMTS 13 binding sites and allowing cleavage of the multimers; can occur in a narrow vessel or in pts with cardiac valvulopathies 3. Lymphoproliferative diseases: Production of anti-von willebrand antibodies can decrease the conc of circulating vWF multimers. The function of the vWF may be inhibited. The vWF antibody compleses are rapidly cleared from circulation; 4. Plasmin levels are increased in Disease states like Pancreatitis, DIC, Decompensated cirrhosis; plasmin not only degrades plasma proteins that compose fibrin, it also cleaves vWF multimers leading to a deficienct state. 5. Certaing Tumors aberrantly express GP1B receptors that bind to vWF multimers; these complexes are subsequently removed from circulation making them unavailable for clotting; abberant receptor expression is found in multiple myeloma for example.1. Hypothyroidism: A fall in production of thyroid hormones can result in a decrease in cellular metabolism and therefore lowered synthesis of von Willebrand factor 2. Mechanical/Shear Stress: They uncoil vWF multimers, exposing ADAMTS 13 binding sites and allowing cleavage of the multimers; can occur in a narrow vessel or in pts with cardiac valvulopathies 3. Lymphoproliferative diseases: Production of anti-von willebrand antibodies can decrease the conc of circulating vWF multimers. The function of the vWF may be inhibited. The vWF antibody compleses are rapidly cleared from circulation; 4. Plasmin levels are increased in Disease states like Pancreatitis, DIC, Decompensated cirrhosis; plasmin not only degrades plasma proteins that compose fibrin, it also cleaves vWF multimers leading to a deficienct state. 5. Certaing Tumors aberrantly express GP1B receptors that bind to vWF multimers; these complexes are subsequently removed from circulation making them unavailable for clotting; abberant receptor expression is found in multiple myeloma for example.

19. Von Willebrand disease Quantitative Type 1 partial vWF deficiency Type 3: complete vWF deficiency Qualitative Type 2: 2A: decreased affinity of vWF for platelet 2B: increased affinity of vWF for platelet 2M: decreased platelet dependent function 2N: defective factor VIII binding site Type 1 von Willebrand disease, which accounts for 70-80% of cases, is characterized by a partial quantitative decrease of qualitatively normal von Willebrand factor and FVIII An individual with type 1 von Willebrand disease generally has mild clinical symptoms, Inherited as an autosomal dominant trait; however, penetrance may widely vary in a single family. Labs: a proportional reduction in von Willebrand factor activity, von Willebrand factor antigen, and FVIII is observed in type 1 von Willebrand disease. Responds to DDAVP - stimulates cells to produce vWF Type 3 is the most severe form of von Willebrand disease. Marked deficiencies of both von Willebrand factor and FVIIIc in the plasma, Absence of von Willebrand factor from both platelets and endothelial cells, Lack of response to DDAVP. Characterized by severe clinical bleeding Inherited as an autosomal recessive trait. Consanguinity is common in kindreds with this variant. Less severe clinical abnormalities and laboratory abnormalities may be identified in occasional heterozygotes; however, such cases are difficult to identify. Type 2 disease accounts for 15-20% of von Willebrand disease cases. Primarily qualitative defects of von Willebrand factor. Can be either autosomal dominant or autosomal recessive. Of the 4 described type 2 von Willebrand disease subtypes (ie, 2A, 2B, 2M, 2N), type 2A von Willebrand disease is by far the most common.? Type 2A: Loss of function mutation on vWF Results in in vivo proteolytic degradation of the von Willebrand factor. Reduced ristocetin cofactor activity + presence of multimeric abnormalities on platelet and plasma von Willebrand factor Characterized by normal-to-reduced plasma levels of factor VIIIc (FVIIIc) and von Willebrand factor. Relative reduction in intermediate and high molecular weight multimer complexes. Type 2B: gain of function mutation on vWF Abnormal vWF has an increased affinity for platelet glycoprotein Ib Reduction in the proportion of high molecular weight von Willebrand factor multimers Increased in low molecular weight fragments are increased. Type 2M: rare Lab results are similar to those of certain patients with type 2A von Willebrand disease. Decreased platelet-directed function, not due to a decrease of high molecular weight multimers. Labs: decreased von Willebrand factor activity, but normal von Willebrand factor antigen, FVIII, and multimer analysis. Type 2N: also rare Defect in FVIII binding site Characterized by a markedly decreased affinity of von Willebrand factor for FVIII Autosomal recessive Results in FVIII levels reduced to usually around 5% of the reference range. Other von Willebrand factor laboratory parameters (ie, von Willebrand factor antigen [VWF:Ag], ristocetin cofactor activity) are usually normal. Type 1 von Willebrand disease, which accounts for 70-80% of cases, is characterized by a partial quantitative decrease of qualitatively normal von Willebrand factor and FVIII An individual with type 1 von Willebrand disease generally has mild clinical symptoms, Inherited as an autosomal dominant trait; however, penetrance may widely vary in a single family. Labs: a proportional reduction in von Willebrand factor activity, von Willebrand factor antigen, and FVIII is observed in type 1 von Willebrand disease. Responds to DDAVP - stimulates cells to produce vWF Type 3 is the most severe form of von Willebrand disease. Marked deficiencies of both von Willebrand factor and FVIIIc in the plasma, Absence of von Willebrand factor from both platelets and endothelial cells, Lack of response to DDAVP. Characterized by severe clinical bleeding Inherited as an autosomal recessive trait. Consanguinity is common in kindreds with this variant. Less severe clinical abnormalities and laboratory abnormalities may be identified in occasional heterozygotes; however, such cases are difficult to identify. Type 2 disease accounts for 15-20% of von Willebrand disease cases. Primarily qualitative defects of von Willebrand factor. Can be either autosomal dominant or autosomal recessive. Of the 4 described type 2 von Willebrand disease subtypes (ie, 2A, 2B, 2M, 2N), type 2A von Willebrand disease is by far the most common.? Type 2A: Loss of function mutation on vWF Results in in vivo proteolytic degradation of the von Willebrand factor. Reduced ristocetin cofactor activity + presence of multimeric abnormalities on platelet and plasma von Willebrand factor Characterized by normal-to-reduced plasma levels of factor VIIIc (FVIIIc) and von Willebrand factor. Relative reduction in intermediate and high molecular weight multimer complexes. Type 2B: gain of function mutation on vWF Abnormal vWF has an increased affinity for platelet glycoprotein Ib Reduction in the proportion of high molecular weight von Willebrand factor multimers Increased in low molecular weight fragments are increased. Type 2M: rare Lab results are similar to those of certain patients with type 2A von Willebrand disease. Decreased platelet-directed function, not due to a decrease of high molecular weight multimers. Labs: decreased von Willebrand factor activity, but normal von Willebrand factor antigen, FVIII, and multimer analysis. Type 2N: also rare Defect in FVIII binding site Characterized by a markedly decreased affinity of von Willebrand factor for FVIII Autosomal recessive Results in FVIII levels reduced to usually around 5% of the reference range. Other von Willebrand factor laboratory parameters (ie, von Willebrand factor antigen [VWF:Ag], ristocetin cofactor activity) are usually normal.

20. Lab Findings

21. Case 2 HPI: A 2-year old boy was brought to the emergency department by his mother for oozing blood from his mouth following a fall nearly 6 hours ago. His mother related that he tended to bleed for prolonged periods from his immunization sites, but there was no history of bruising or hematomas. The patient was on antibiotics for a recent ear infection. There was no known family history of a bleeding disorder. PE: Gen: Alert, in no apparent distress, development appropriate for age HEENT: Two small lacerations on the inside of lower lip, oozing bloodRemainder of exam within normal limits (notably, no petechia, bruises, joint swelling)

22. What is your DDx? Von Willebrand disease Factor VIII and IX deficiency (Hemophilia A, B) Lupus anticoagulant, factor VIII inhibitor (rare) Factors XI and XII deficiency (rare)

23. Initial lab results

24. Additional Work up

25. Final Diagnosis Von Willebrand Disease

26. References Cuker A, Connors JM, Katz JT, Levy BD, Loscalzo J; A Bloody Mystery, N Engl J Med 2009; 361:1887 - 94 Haberichter SL, Balistreri M, Christopherson P, Morateck P,Gavazova S, Bellissimo DB, Manco-Johnson MJ, Gill JC, Montgomery RR; With type 1 von Willebrand disease with decreased VWF survival Assay of the von Willebrand factor (VWF) propeptide to identify patients, Blood 2008; 108:3344 - 3351 Robbins and Cotran Pathological Basis of Human Disease, 7th ed. Chapter 13 (pg 649 - 659) Harrison’s Principles of Internal Medicine, 16th ed. Chapter 102 http://path.upmc.edu/cases/case325.html Kroonen LT, Gillingham BL Provencher MT, Orthopedic Manifestations and Management of Patients With von Willebrand Disease, Orthopedics 2008; 31:263