Bleeding Disorders Flashcards
Describe the elements of the history and physical exam that are important for clinical evaluation of bleeding disorders.
History = often most informative part!
Bleeding from single or multiple sites?
Pattern of bleeding
• Skin and mucosal surfaces → thrombocytopenia or defect in platelet or vWF
• Oral mucosal blood blisters → severe thrombocytopenia
• Deep tissue bleeding → defect in soluble coagulation factor response
• Retroperitoneal bleeding or hemarthrosis → defects in secondary hemostasis
Previous hemostatic challenges (ex: surgery, major trauma, tooth extractions)
History of chronic anemia
Family history of bleeding problems
Medications in past 1-2 weeks
• Especially aspirin, NSAIDs or other anti-platelets, cold meds, alcohol use, herbal remedies
Underlying medical conditions (ex: liver disease, uremia)
Physical exam
o Skin:
• Petechiae (hemorrhage of small blood vessels; can occur spontaneously with low platelets)
• Ecchymosis (bruise)
• Hematoma = clotting factor deficiency
• Spider angiomas and palmar erythema = liver disease
o Oral mucosa
o Splenomegaly
o Joint deformities (chronic arthropathy → hemophilia)
Describe the relationship between platelet count and bleeding risk in conditions associated with decreased production or increased destruction of platelets.
• Mild (60-150 k/μl) = asymptomatic
• Moderate (20-50 k/μl) = bleeding in response to trauma or surgery
• Severe (less than 20 k/μl) = spontaneous bleeding symptoms (petechiae, bruising)
When <10 k/μl → risk of life-threatening hemorrhage, may need platelet transfusions
Treatment of thrombocytopenia:
Platelet transfusion = most useful in treating due to marrow failure
• Also commonly used in cardiac surgery, liver transplantation
• Transfused platelets survive 2-3 days
• Shorter survival in consumptive thrombocytopenia or if alloimmunized patient
• Alloimmunized patients may need HLA-matched platelets
Causes of failure of platelet production
o Congenital (rare) o Primary bone marrow disorders: leukemia, aplastic anemia, myelodysplastic syndrome o Secondary bone marrow suppression: cytotoxic drugs, radiation, viral infection, nutritional deficiencies, marrow replacement by fibrosis, malignancy
Platelet sequestration by spleen
o Larger spleen = sequesters more platelets
o Ex: hematologic malignancies, secondary enlargement due to liver disease with portal vein HT
Increased platelet destruction/utilization
o Immune-mediated: ITP, drugs, autoimmune disease, viral infection (HIV)
o Non-immune mediated: sepsis, DIC, TTP
Causes of defective primary hemostasis with normal platelet count:
Abnormal vessels
Platelet dysfunction Inherited disorders (rare, recessively inherited) • Glanzmann’s Thrombasthenia = platelets lack fibrinogen receptor (GpIIb/IIIa) → unable to aggregate • Bernard-Soulier Syndrome = platelets lack vWF receptor (GpIb) → unable to adhere; platelet count usually low Drugs • Aspirin = irreversibly inhibits cyclooxygenase → blocks thromboxane synthesis • Clopidogrel (Plavix) = blocks ADP receptor • Others: Abciximab, Eptifibatide, tirofiban = block IIb/IIIa receptor → prevents aggregation Uremia Monoclonal gammopathy (myeloma, Waldenstroms) = protein interferes with platelet adherence or aggregation Myelodysplasia and myeloproliferative disorders = abnormal stem cells
Lack of vWF
Acquired coagulation inhibitors and lab findings
Includes:
Antibodies to clotting factors (usually VIII)
• Hemophiliacs = alloimmune → blocks therapeutic effect of clotting factor infusion
• Others = autoimmune → may cause severe bleeding
• “Acquired hemophilia”
Drugs
• Heparin and related drugs
• Accelerate inhibition of thrombin and/or Xa by antithrombin
• Direct thrombin and Xa inhibitors
• Ex: lepirudin, argatroban, dabigatran, rivaroxaban, apixaban
Lupus anticoagulant
• Binds to phospholipid → prevents catalysis of clotting cascade
• Anticoagulant effect in vitro only
• Does not cause bleeding
• Can promote thrombosis by uncertain mechanism
Lab findings Prolonged clotting time = Does NOT correct with mixing study Heparin • aPTT = used to monitor drug • Thrombin time = most sensitive • PT/INR at high levels Factor VIII inhibitors • aPTT only Lupus anticoagulant • aPTT • Occasionally PT/INR
Immune/Idiopathic Thrombocytopenic Purpura: features
o Most common cause of isolated thrombocytopenia
o Ab’s coat platelets → macrophages recognize Fc portion → rapid destruction in liver and spleen
o Typically = platelet production is normal or increased
Childhood form:
• Self-limited
• Often follows viral infection: viral-IgG complex adheres to platelets → destruction
Adult form:
• Usually chronic or recurring
• More often a true autoimmunity
• In pregnant women = maternal Ab IgG can cross placenta → neonatal thrombocytopenia
Diagnosis of exclusion:
• Rule of other causes
• No reliable Coombs test or analog of retic count for platelets
Immune/Idiopathic Thrombocytopenic Purpura: treatment
- Mild cases = observation
- 1st line = corticosteroids
- Other treatments: IVIG, splenectomy, immunosuppressant drugs (ex: ritixumab)
Synthetic thrombopoietic agents
Eltromopag
o TPO receptor agonist
o Once daily oral dosing
Romiplostim
o Peptibody: Ig heavy chain linked to peptide analog of thrombopoietin
Both drugs = increase risk of reticulin fiber deposition in bone marrow with prolonged use
Drug-induced thrombocytopenia
o Most common from antibiotics (penicillin, sulfonamide-related) and quinine compounds
MOA:
• Drug binds platelet → allows preformed antibodies to stick to platelets (induced fit)
• Drug-dependent Ab-mediated destruction of platelets
• Sudden, severe onset of thrombocytopenia
• Does not require prior exposure
Treat:
• Stop all non-essential drugs
• Recovery ~5-7 days after stopping
Note: Heparin- induced thrombocytopenia occurs by different mechanism (more likely to cause thrombosis than bleeding)
Describe the pathophysiology, genetics, and the clinical and laboratory characteristics of the most common form of von Willebrand disease (type I vWD).
• Common inherited bleeding disorder
• Autosomal dominant inheritance with variable penetrance
o Quantitative decrease in vWF
o Proportional decrease in factor VIII (because carried by vWF in blood)
Characterized:
o Mild to moderate bleeding tendency:
• Menorrhagia, bleeding after surgery, bruising
o Mucocutaneous bleeding
o May also have soft tissue/joint bleeding
Lab findings:
o Defective platelet adherence (PFA-100 or long bleeding time)
o Subnormal levels of vW antigen and activity; low levels VIII
o PTT may be prolonged with VIII low enough (<30%)
Treatment o DDAVP (desmopressin) → stimulates endogenous vWF release from endothelial cells o If mucocutaneous bleeding = may give anti-fibrinolytic agents
Hemophilia A and B: genetics
o X-linked deficiencies (genetically heterogeneous)
o Factor levels in female carriers vary due to random X chromosome inactivation
o 20% of cases due to new mutation
A = in factor VIII
• Represents 80-85% of congenital hemophilia
• More common due to “nested” gene within, also located elsewhere on chromosome, so prone to gene crossover/flips
B = in factor IX
Factor levels in female carriers vary due to random X chromosome inactivation
o 20% of cases due to new mutation
Hemophilia A and B: clinical characteristics
Severity depends on factor’s activity:
Severe = <1%
• Spontaneous bleeds into joints and deep tissue
• Require ongoing factor replacement
• May develop high titer inhibitors (Abs against transfused clotting factor)
Moderate = 1-5%
• Bleeds more often precipitated by minor trauma
Mild = 5-30%
• Asymptomatic until challenged by significant trauma or surgery
Joints and muscles = most common bleeding sites
• Repeated bleeds → permanent joint and nerve damage
• Cycle of hemophilic arthropathy:
Hemophilia A and B: lab findings and treatment
Lab findings
o Long aPTT
• Corrects with mixing with normal plasma
o Normal PT/INR
o Low level of factor VIII or IX activity (0-30% activity)
Treatment
o Factor replacement
Vitamin K deficiency: causes
• Fat-soluble vitamin in many foods and also made by gut bacteria
Function = create Ca2+ binding sites on:
o Clotting factors: II, VII, IX, X
o Anticoagulant proteins: protein C, protein S
Causes of deficiency:
1) Inadequate supply:
Newborn (hemorrhagic disease of newborn)
• More vulnerable to deficiency due to poor Vit K transport across placenta, lack of gut bacteria colonization, and poor Vit K amounts in breast milk
Presentations:
o Very early: day 1 of life; intracranial hemorrhage
o Early: days 1-7; GI bleeding and ecchymosis
o Late: weeks 1-3; with complicating GI illness like CF, alpha-1 antitrypsin deficiency, diarrhea; associated with intracranial bleeding, umbilical cord bleeding, or ecchymosis
• Prophylactic treatment with Vit K injection on 1st day of life
Hospitalized patient = not eating, on antibiotics
2) Poor absorption
• Biliary obstruction
• Generalized malabsorption (Celiac disease, Crohn’s disease, resection of small bowel)
3) Vit K inhibitors
• Warfarin (Coumadin)
Vitamin K deficiency: lab findings
o Long PT/INR (more sensitive)
o Long aPTT
o Long clotting times correct with mixing with normal plasma
o Low blood levels of Vit K dependent factors; others normal
Vitamin K deficiency: treatment
o Oral or parenteral Vit K
• Replenish factors within 12-24 hrs
• Need 2-3 days for maximum effects
Be able to explain how to use laboratory tests to distinguish coagulation factor deficiency from an inhibitor of coagulation.
Bleeding time
o Poorly standardized
PFA-100 (Platelet function screen)
o Measures ability of platelets to adhere to collagen and aggregate under flow
o Replaces bleeding time
Platelet aggregometry o Measures platelet aggregation in test tube in response to various agonists o Expensive o Labor intensive o Doesn’t test platelet adhesion
Disseminated intravascular coagulation (DIC): pathophysiology
o Uncontrolled, disorganized activation of clotting and fibrinolytic systems
• Rapid formation and lysis of intravascular fibrin
o Usually caused by exposure of blood to excessive amounts of tissue factor
o Leads to consumption of clotting and fibrinolytic enzymes and inhibitors, platelets
o Associated with diffuse endothelial injury
Disseminated intravascular coagulation (DIC): Clinical features
Associated with underlying life-threatening diseases:
• Sepsis, disseminated cancer, obstetric complications, severe liver disease, acute hemolytic transfusion reactions, surgery, shock
Bleeding and/or tissue injury may occur
Pupura fluminans
• Tissue necrosis and multiple organ failure
• Most often in severe sepsis
Contributing factors (mainly cytokine-mediated):
• Tissue hypoperfusion (shock)
• Endothelial injury
• Intravascular fibrin formation
Disseminated intravascular coagulation (DIC): lab findings and treatment
o Thrombocytopenia o Long PT/INR o Long PTT o Elevated D-dimer o Low fibrinogen o RBC fragmentation
Treat = control underlying disease
Microangiopathic hemolytic anemia
Characterized: • Presence of RBC fragments (Schistocytes) on peripheral smear • Anemia • Elevated LDH • Usually elevated retic count
Type of intravascular hemolysis
• Deposition of thrombi in small vessels → RBC destruction
• Also due to diffuse endothelial injury
If Coagulopathy (prolonged coagulation times): • Present → DIC • Absent → TTP, HUS or diffuse endothelial injury
Thrombotic thrombocytopenia (TTP)
Widespread formation of platelet aggregates in small vessels
• Platelets clumped together via unusually large vWF factor multimers
Caused by autoimmune destruction of ADAMTS13
• Normally breaks down large multimers
Results: • Microangiopathic hemolytic anemia • Thrombocytopenia • Multiple organ dysfunction • Note: NO consumption of clotting factors (different than DIC)
Blood smear
• Schistocytes (RBC fragments)
• Absence of platelets
Lab findings
• Very high LDH due to intravascular hemolysis
• Low haptoglobin
• Thrombocytopenia and anemia
• Hemoglobinemia, hemoglobinuria
• Evidence of renal dysfunction (increased creatinine, proteinuria, hematuria)
• Very low (less than 5%) ADAMTS13 activity with circulating inhibitor in most cases
• Coagulation assays usually normal
• Very high mortality rate if untreated (over 90%)
Treat:
• Plasma exchange = replaces ADAMTS13; removes autoantibody
• Often give immunosuppressive therapy
• Now: mortality <20%
Hemolytic Uremic syndrome (HUS)
o Microangiopathic syndrome
o Similar to TTP but kidneys are main affected organ
Associated with GI prodrome
• Due to infection toxin-producing E. coli O157:H7
• Shiga-like toxin injures endothelium → microangiopathy and renal failure
• May occur in epidemics due to contaminated food
o Often self-limited
o Susceptible patients (children, elderly) may have life-threatening disease
Note: sporadic HUS not associated with infection
• Often associated with inherited defects in complement regulation (“atypical HUS”)
