Pathology Notes

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

Hemolytic-uremic syndrome   Updated: 07/25/2023 © Jun Wang, MD, PhD General features Most common cause of acute kidney injury in children Associated with Shiga-like toxin More common in summer Need to differentiated from TTP Clinical presentations Usually with history of bloody diarrhea Progressive renal failure Microangiopathic (nonimmune, Coombs-negative) hemolytic anemia Thrombocytopenia Neurological presentation less common Key risk factors Bacterial infection, most commonly due to E coli (O157:H7 most common), S dysenteriae, Salmonella typhi, etc “Atypical” HUS Similar clinical presentation but NOT associated with Shiga-like toxin Commonly in adults May occur in any season Usually NO history of bleeding diarrhea Probably genetic defects in complement factor H , membrane cofactor protein (CD46 ), or factor I Excessive activation of complement pathway Poor prognosis, rapid progress to renal failure Key pathogenesis Endothelial injury caused by

Thrombotic thrombocytopenic purpura Updated: 07/25/2023 © Jun Wang, MD, PhD General features Thrombocytopenia resulted from small vessel thrombosis Need to be differentiated from hemolytic-uremic syndrome Clinical presentations Pentad Microangiopathic hemolytic anemia Thrombocytopenic purpura Neurologic abnormalities: Alteration of mental status, seizures, hemiplegia, paresthesias, visual disturbance, and aphasia Fever Renal disease : Abnormal renal functions May have history of bloody diarrhea, need to differentiate from HUS Key pathogenesis ADAMTS13 (Adam is 13) deficiency associated ultra-large von Willebrand factors Deficiency can be either congenital or due to autoantibodies Endotoxic (Escherichia coli O157:H7 and Shigella dysenteriae serotype I) induced endothelial cell secretion of ultra-large von Willebrand factors Ultra-large von Willebrand factors tends to promote platelet adhesion and aggregate, resulting in thro

HIV associated thrombocytopenia Updated: 07/24/2023 © Jun Wang, MD, PhD General features Most common cause of thrombocytopenia in HIV-infected patients Either direct HIV infection of hematopoietic stem cells or immune process Clinical presentations HIV test may be considered in patient with unexplained thrombocytopenia May have splenomegaly Key pathogenesis Probably ineffective platelet production and increased peripheral platelet destruction Key Laboratory findings Thrombocytopenia Other findings associated with HIV infection Back to thrombocytopenia Back to bleeding disorders Back to contents

Heparin-induced thrombocytopenia Updated: 07/24/2023 © Jun Wang, MD, PhD General features Complication of heparin therapy More commonly associated with unfractionated heparin (UFH) than low molecular weight heparin (LMWH) Type I :   Presents within the first 2 days after exposure to heparin , and the platelet count normalizes with continued heparin therapy, nonimmune disorder resulted from direct effect of heparin on platelet activation Type II :   Immune-mediated disorder, typically occurs 4-10 days after exposure to heparin , life- and limb-threatening thrombotic complications, THE HIT when discussed   Diagnosis based on History of heparin usage Clinical presentations of thromboembolism Thrombocytopenia   Laboratory studies of HIT antibodies Clinical presentations Thromboembolism Most commonly venous thrombosis 4Ts T hrombocytopenia T iming of platelet count drop, typically 5-14 days, or less in one day if previously exposed to heparin T hrombosi

Chronic immune thrombocytopenia   Updated: 07/24/2023 © Jun Wang, MD, PhD General features Typically in adults aged 20-40 years More common in women Usually do not have history of viral infection Associated with alterations in immune homeostasis Diagnosis of exclusion in patients with isolated thrombocytopenia Clinical presentations Insidious onset, usually NO precipitating causes Most commonly bleeding in skin or mucosa Severe hemorrhage uncommon May have splenomegaly Key pathogenesis Clonal expansion of CD8+ cytotoxic T cells may act independently of autoantibodies Autoantibodies against platelet GPIIb/IIIa or GPIb/IX Reduced platelet lifespan due to antibody-mediated destruction   Impaired platelet production due to megakaryocytes damage Key Laboratory findings Isolated thrombocytopenia Positive anti-platelet antibodies Negative anti-platelet tests could NOT rule out ITP Key morphological features Normal to increased megakaryocytes Need to ex

Acute immune thrombocytopenia   Updated: 07/24/2023 © Jun Wang, MD, PhD General features Self-limited, usually weeks Almost exclusively in children Usually preceded by a viral infection (varicella, mononucleosis) or vaccination Usually clinical diagnosis based on Well appearing patient Mucocutaneous bleeding No systemic signs Isolated thrombocytopenia Clinical presentations Sudden onset Presentations depending on platelet count Mild bleeding/petechiae, unless platelet < 20 x 10 3 /mm 3 NOT ITP if with lymphadenopathy or splenomegaly, usually suggestive of secondary thrombocytopenia Key pathogenesis May be associated with auto-reactive cytotoxic T cells, or autoantibodies against platelet membrane components Probably due to exposure of cryptantigens or pseudoantigens Key Laboratory findings Isolated thrombocytopenia Key morphological features Megakaryocyte hyperplasia Back to thrombocytopenia Back to bleeding disorders Back to conten

Reactive thrombocytosis Updated: 08/12/2020 © Jun Wang, MD, PhD Etiology Infection Postsurgical status Malignancy Postsplenectomy state Acute blood loss or iron deficiency Clinical features No need to correct platelet count Back to bleeding disorders Back to contents

Bleeding disorders due to abnormal platelet function Updated: 08/12/2020 © Jun Wang, MD, PhD General features Inherited or acquired Three large categories Defects of adhesion Defects of aggregation Disorders of platelet secretion Glanzmann’s disease Qualitative or quantitative deficiencies of the fibrinogen receptor GPIIb/IIIa Platelet type bleeding of mucosa, skin, etc Management: Avoidance of medications that affect platelet function, treatments of anemia, etc Platelet transfusion for bleeding patients Recombinant Factor VIIa may be considered Bernard-Soulier Syndrome Group of hereditary platelet disorders characterized by Thrombocytopenia Giant platelets Qualitative platelet defects Absence or decreased expression of the GPIb/IX/V complex , a receptor for von Willebrand factor, on the surface of the platelets Autosomal recessive Clinical presentations: Easy bruising, bleeding Treatment: Supportive, may consider DDAVP, or similar approach

Thrombocytopenia   Updated: 08/03/2021 © Jun Wang, MD, PhD General features Platelet count below the lower limit of normal, either reduced production or increased destruction Grades Mild (platelet count 100-150 x 10 3 /mm 3 ) Moderate (50-99 x 10 3 /mm 3 ) Severe (<50 x 10 3 /mm 3 ) Usually asymptomatic until platelet count <100 x 10 3 /mm 3 Surgical bleeding <50 x 10 3 /mm 3 Spontaneous bleeding <10 x 10 3 /mm 3 Clinical presentations Asymptomatic, ISOLATED, incidentally-discovered thrombocytopenia Common: Immune thrombocytopenia (ITP) , Gestational thrombocytopenia during pregnancy Less common: Occult liver disease, myelodysplastic syndrome , congenital thrombocytopenia, HIV infection Symptomatic, severe thrombocytopenia Drug-induced thrombocytopenia Immune thrombocytopenia (ITP) Thrombocytopenia as part of a multisystem illness Common : Immune thrombocytopenic purpura, drug-induced thrombocytopenia, heparin-induced thrombocytopenia

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

Terms of skin disorders Updated: 02/11/2022 © Jun Wang, MD, PhD     Clinical Angioedema : Abrupt edematous changes of skin or mucosa, similar to urticaria Changes of darkness of skin : Hyperpigmentation : Darker than normal surrounding skin Hypopigmentation : Lighter than normal surrounding skin Crust : Hardened layer of a mixture of serum, blood, or purulent exudates, associated with erosion, or ulcer Cyst : Encapsulated cavity or sac lined by true epithelium Flat colored lesions : Macule : Circumscribed flat area of discoloration < 1 cm Patch : Flat area of discoloration > 1 cm Lesions with discontinuous surface : Fissure : Crack through the epidermis and into the dermis, NO tissue loss Erosion : Discontinuity of skin causing partial loss of epidermis Excoriation : Deep linear scratch, commonly self-induced Ulceration : Discontinuity of skin causing complete loss of epidermis and possible loss of dermis Lichenification : Thickening of sk