Pathology Notes

Practice questions answers Coagulopathy  © Jun Wang, MD, PhD 1. E. Bleeding disorders with normal platelet counts are commonly associated with coagulation factor abnormalities, either due to factor deficiency or presence of inhibitors. Correction of PT or PTT by mixing studies rules out presence of inhibitors, usually antibodies against coagulation factors. Liver disease associated coagulopathy usually have prolonged PT and PTT. Renal function abnormality can be seen in thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome and atypical hemolytic-uremic syndrome . Vitamin B12 and folate deficiencies are associated with megaloblastic anemia. These are less likely due to normal CBC. 2. B. Factor VIII is low in patients with von Willebrand disease , since von Willebrand factors are carriers of factor VIII. Lacking of von Willebrand factors will influence stabilization of factor VIII. This is less likely to be either Hemophilia A or Hemophilia B since the later tw

Practice questions Coagulopathy © Jun Wang, MD, PhD 1. Use this case for the next four questions . A 3-year-old boy presents with oozing bleeding from his mouth after a fall 2 hours ago. He has a history of easy bruising since birth. He had an episode of low-grade fever 1 week ago, that was relieved after his parents gave him aspirin. His past history is otherwise unremarkable. Vaccination is up to dates. Physical examination reveals a few bruises on his legs. No other abnormality is seen. Laboratory tests reveal an aPTT of 36 second (normal range: 24.4-32.3 second). His CBC, PT are all normal. Mixing study for aPTT is 30.5 second (normal range: 28.2-38.1 second). What additional study would be most helpful for making a diagnosis? A. Liver function tests B. Renal function tests C. Serum autoantibodies for coagulation factors D. Serum vitamin B12 and folate levels E. von Wellibrand factor activity, factors VIII and IX 2. A 3-year-old boy presents with oozing ble

Bleeding disorders associated with vitamin K deficiency Updated: 07/25/2023 © Jun Wang, MD, PhD General features Bleeding disorders due to nutritional vitamin K deficiency or warfarin use Clinical presentations History of nutritional deficiency or warfarin use Easy bruising Soft tissue hematoma Other bleeding symptoms Key risk factors Fat malabsorption syndromes (vitamin K is a fat soluble vitamin) Malnutrition Antibiotics (destroy bacteria producing vitamin K or interfere with vitamin K carboxylation) Newborn: Lack of VK in breast milk, or malabsorption caused by cholestasis, etc Warfarin associated inhibition of regeneration of the active form of vitamin K For Warfarin using patients: > 65, other conditions (atrial fibrillation, GI bleeding, cerebrovascular disease, etc), concomitant medications (aspirin, amiodarone) Key pathogenesis Impaired production of active factors II, VII, IX and X and proteins C and S Warfarin inhibits vitamin K reductas

Disseminated intravascular coagulation (DIC) Updated: 07/25/2023 © Jun Wang, MD, PhD General features Acquired syndrome arising from various causes Characterized by systemic, massive, sustained and excessive activation of coagulation High risk of life threatening bleeding Diagnosed based on clinical presentation and laboratory findings Clinical presentations Symptoms associated with tissue ischemia Acute renal failure Jaundice due to liver dysfunction Acute lung injury: Hemorrhage, acute respiratory distress syndrome Neurological dysfunction: Change of mental status Adrenal failure: Due to adrenal hemorrhage or infarction Multiple organ dysfunction Bleeding, thrombosis, or both Acute: Usually hemorrhage, such as petechiae, ecchymosis Chronic: Venous thromboembolism more common Etiology Infection/sepsis: Most common, includes bacterial, viral, fungal, rickettsial and protozoal organisms Tissue damage: Trauma (2nd most common, head injury or exten

Liver disease associated coagulopathy Updated: 07/25/2023 © Jun Wang, MD, PhD General features Multiple factor deficiency due to impaired production in liver Vitamin K deficiency may exacerbate deficiency of VK associated factors (II, VII, IX, X) Two factors not affected by abnormal liver function Factor VIII produced by endothelial cells Factor XIII, produced in bone marrow Clinical presentations Bleeding Thrombosis: Decreased plasminogen, protein C and protein S   Presentations associated with liver failure, such as esophageal varices Key pathogenesis Impaired production of coagulation factors Key Laboratory findings Prolongations of aPTT, PT, INR Mild thrombocytopenia Elevated D-dimer Normal level of factor VIII Differential diagnosis TTP : Clinical setting, normal PT and PTT, low ADAMTS13 HIT : History of heparin usage, normal PT, aPTT and fibrinogen, antibodies against PF4 DIC : Usually reduced levels of factor VIII Back to bleed

Acquired hemophilia Updated: 07/25/2023 © Jun Wang, MD, PhD General features Rare but potentially life-threatening bleeding disorder Associated with autoimmune disorders , solid tumors, hematologic malignancies, dermatologic disorders, inflammatory bowel disease, respiratory diseases, diabetes, acute hepatitis (B and C), severe drug reactions, post-childbirth, or previous usage of coagulation factors Clinical presentations Bleeding Hemarthrosis uncommon Key pathogenesis Autoantibodies (inhibitors) directed against plasma coagulation factors Most frequently factor VIII (FVIII) Key laboratory findings Prolonged aPTT NOT reversed on a mixed study Reduced FVIII levels and evidence of an FVIII inhibitor Normal PT, platelet count Treatment Treat underlying disorder Desmopressin in very low titer inhibitors High-dose Factor VIII is low titer inhibitors Recombinant Factor VIIa for severe bleeding Back to bleeding disorders Back to contents

Hemophilia B Updated: 07/25/2023 © Jun Wang, MD, PhD General features AKA Christmas disease X-linked recessive Less common than Hemophilia A May be result of spontaneous mutation Almost exclusively affects males Clinical presentations Easy bruising Bleeding into joints (hemarthrosis), soft tissue, GI/ GU tract Excessive bleeding after surgery Mild: > 5% factor VIII activity, bleeding after trauma or surgery Moderate: 1% - 5% activity; bleeding after surgery or trauma, may have spontaneous bleeding Severe: < 1% activity; spontaneous bleeding, may be life-threatening Key pathogenesis Factor IX deficiency Presentation in female patients due to High degree of X-inactivation Homozygosity Hemizygosity in Turner syndrome May be caused by inhibitory antibodies against factor IX Key Laboratory findings Normal to prolonged aPTT Reduced factor IX Mild: > 5% Moderate: > 1-5% Severe: < 1% Usually normal platelet count, PT Mixin

Hemophilia A Updated: 07/25/2023 © Jun Wang, MD, PhD General features Most common congenital bleeding disorder X-linked recessive May be result of spontaneous mutation Almost exclusively affects males Clinical presentations Easy bruising Bleeding into joints (hemarthrosis), soft tissue, GI/ GU tract Excessive bleeding after surgery Mild: > 5% factor VIII activity, bleeding after trauma or surgery Moderate: 1% - 5% activity; bleeding after surgery or trauma, may have spontaneous bleeding Severe: < 1% activity; spontaneous bleeding, may be life-threatening Key pathogenesis Factor VIII deficiency Presentation in female patients due to High degree of X-inactivation Homozygosity Hemizygosity in Turner syndrome May be caused by inhibitory antibodies against factor VIII Key Laboratory findings Prolonged PTT, depending on severity Reduced factor VIII Mild: > 5% Moderate: > 1-5% Severe: < 1% Usually normal platelet count, PT

Hemophilia arthropathy Updated: 07/25/2023 © Jun Wang, MD, PhD General features Permanent joint disease due to repeated haemarthrosis Clinical presentations Usually large joints Either monoarticular or oligoarticular Pain   Dysfunction Key pathogenesis Reactive proliferation and regeneration of chronically inflamed synovium, due to repeated hemorrhagic damage Key morphological features Synovial hyperplasia, chronic inflammation Fibrosis Cartilage erosion Subarticular cysts Back to bleeding disorders Back to  contents

Von Willebrand’s disease Updated: 07/25/2023 © Jun Wang, MD, PhD General features Most common hereditary bleeding disorder No gender preference, but females tend to be symptomatic with the same von Willebrand Factor (vWF) level Due to deficiency or dysfunction of vWF, which has two functions: Mediating platelet adherence to subendothelium Carrier molecule for Factor VIII, which protects it from premature destruction Bleeding exacerbated by aspirin Phenotypes Type 1, partial quantitative deficiency of vWF but normal function Most common, autosomal dominant   Type 2, qualitative defects 4 subtypes*: A, B, M, N Autosomal dominant (B), recessive (N), or either (A, M) Most common subtype: 2A Type 3, severe or complete vWF deficiency Very rare Autosomal recessive Clinical presentations Similar to platelet dysfunction : nose bleeding, easy bruising, etc Type 1 Mild/moderate bleeding Type 2 2A: Moderate to severe bleeding 2B: Modera

Bleeding disorders   Updated: 09/16/2020 © Jun Wang, MD, PhD Hemostasis Primary: Vasoconstriction, platelet activation Secondary: Coagulation cascades Results: Blood clot formation Activation of platelets Coagulation system Intrinsic pathway: XII, XI, IX, VIII (8-12 except 10) Extrinsic pathway: VII Common pathway: X, V, prothrombin (II), fibrinogen (I) (4 smallest US dollar bills) Etiology of bleeding disorders Vascular dysfunction, including vitamin C deficiency, telangiectasia, allergic purpura, purpura associated with infections such as meningococcus and Rocky Mountain spotted fever, etc Platelet disorders Thrombocytopenia Thrombocytosis Platelet dysfunctions associated with uremia, MDS , medications (NSAIDs etc) Bernard-Soulier syndrome, etc Coagulopathy Von Willebrand disease Hemophilia A Hemophilia B Acquired hemophilia Liver disease associated coagulopathy Vitamin K deficiency, including warfarin associated coagulopathy Other