Pathology: Hemorrhage And Thrombosis

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subcutaneous hematomas (bruises)

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Ecchymoses

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slightly larger, same associations plus trauma, vasculitis, increased vascular fragility

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Purpura

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minute hemorrhages into skin, mucous membranes, serosal surfaces (esp. associated with locally increased intravascular pressure, thrombocytopenia, defective platelet function)

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Petecchiae

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(activated by thrombin) covalently cross-links and stabilizes the fibrin polymers

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Factor XIIIa

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assesses function of proteins in extrinsic pathway ( factors I (fibrinogen), II, V, VII, and X). Tissue factor and phospholipids are added to citrated plasma (sodium citrate chelates calcium to prevent spontaneous clotting). Coagulation is started by adding exogenous calcium and time for fibrin clot to form is recorded; more useful in monitoring coumadin (warfarin)

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PT – prothrombin time

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assesses the intrinsic pathway (factors I (fibrinogen), II, V, VIII, IX, X, XI, XII). Clotting is initiated by adding negative charged particles (which activates Factor XII), phospholipids, and calcium, and the time to fibrin clot is recorded; more helpful in monitoring heparin therapy

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PTT – partial thromboplastin time

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are vitamin K dependent that act in a complex that proteolytically inactivates factors Va and VIIIa

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Protein C and S

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An intravascular mass attached to the vessel wall and composed of varying proportions of coagulation factors, RBCs, and platelets.

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Thrombus

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Formation of a thrombus

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Thrombosis

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Thrombus that has migrated from its site of origin and causes blockage of a vessel in another part of the body

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Embolism

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pathogenesis of thrombi...

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circulatory stasis ; endothelial injury ; hypercoagulable state ;

VIRCHOW'S TRIAD

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Gelatinous with dark red dependent portion (red cells have settled by gravity) and yellow “chicken fat” upper portion
Not attached to underlying wall
No lines of Zahn
A layer rich in leukocytes

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Postmortem clots

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Primary (genetic) causes of Hypercoagulability
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Factor V Leiden
Prothrombin gene mutation
Methyltetrahydrofolate gene mutation (increased homocysteine)
AT III deficiency
Protein C deficiency
Protein S deficiency

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Inherited cause of hypercoagulability; 2 – 15% of Caucasians
Single-nucleotide (point) mutation: arginine to glutamine substitution at position 506 (n.b. error in Robbins, 8th ed.) which makes factor V resistant to cleavage by protein C
Autosomal dominant (Cleveland clinic)
Antithrombotic counter-regulatory pathway is lost; Factor V serves as cofactor in conversion of prothrombin to thrombin and mutation results in more factor V, shifting balance to more thrombin generation
Heterozygotes have five fold increased relative risk of venous thrombosis; homozygotes 50-fold increase

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Leiden V mutation
**** must know this entire slide

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Single nucleotide change
1 – 2% of population
Patients have elevated prothrombin levels and approximately 3X increased risk of venous thrombosis
Autosomal dominant

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Prothrombin gene mutation
Unknown mechanism of how mutation results in increased prothrombin; hypercoagulability probably because of greater availability of prothrombin to convert to thrombin
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Elevated levels contribute to arterial and venous thrombosis (and development of atherosclerosis)
metabolism of this involves methylenetetrahydrofolate reductase (MTHFR) and methionine synthase

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Homocysteine
Prothrombotic effects may be due to thioester linkages formed between metabolites of homocysteine and some proteins, such as fibrinogen.

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May be caused by inherited deficiency of CBS
More common: Variant form of enzyme 5,10 methylenetetrahydrofolate reductase causes mild forms in 5 to 15% of Caucasian and eastern Asian populations

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Homocysteinemia
Can get acquired hyperhomocysteinemia via folate deficiency, B6 and B12 deficiencies, renal failure, DM, hypothyroidism, CA, pernicious anemia, inflammatory bowel disease or therapy with methotrexate, theophylline, or phenytoin

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Natural anticoagulant protein - primary inhibitor of thrombin; neutralizes serine proteases (Factors XII, XI, IX, X) ; deficiency leads to enhanched thrombin formation
Mutations result in either quantitative or qualitative deficiencies
Autosomal dominant

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Antithrombin III deficiency

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Natural anticoagulant protein
Mutations may result in either quantitative or qualitative deficiencies; cannot inactivate factors V and VIII
Controls formation of thrombin in presence of cofactor Protein S
AD with incomplete penetrance but may be AR with coinheritance of another defect (esp. Leiden factor V)

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Protein C deficiency

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Natural anticoagulant protein – cofactor of Protein C
Mutations can result in quantitative or qualitative deficiencies
AD inheritance

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Protein S deficiency

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Secondary (acquired) causes of Hypercoagulability

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Antiphospholipid antibody syndrome (lupus anticoagulant syndrome)

Heparin-induced thrombocytopenia syndrome

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5 – 14 days following administration of unfractionated heparin
caused by antibodies to complexes between heparin and platelet factor 4 (PF4) induced by the unfractionated heparin
Immune complexes of these antibodies and PF4/heparin bind to the surface of platelets and induce their activation by cross-linking Fc IIA receptors and also bind to the surface of the endothelium, inducing procoagulant activity
Platelets activated with heparin-induced thrombocytopenia (HIT) immunoglobulin G (IgG) increase their release and surface expression of PF4. Thus, a positive feedback loop is created as further release of PF4 with platelet activation occurs.
Platelets are consumed (thrombocytopenia) because there is a prothrombotic state

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Heparin-induced thrombocytopenia syndrome

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Various clinical manifestations include:
recurrent thromboses (venous more common than arterial)
repeated miscarriages (antibody mediated inhibition of t-PA needed for trophoblastic invasion of uterus)
cardiac valve vegetations
thrombocytopenia,
pulmonary embolism, pulmonary hypertension (recurrent PE)
stroke, bowel infarction, renovascular hypertension, renal microangiopathy resulting in renal failure
Highest association with lupus

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Antiphospholipid antibody syndrome

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Effects are mediated through binding of the antibodies to epitopes on plasma proteins (like prothrombin) that are somehow induced by phospholipids (Abs directed against phospholipids bound to plasma proteins)
Autoantibodies (in vivo) cause endothelial injury, activate platelets and complement, and interact with catalytic domains of some coagulation factors. This leads to hypercoagulability
Exact mechanisms are unknown
Rx – may require lifelong coumadin

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APLS

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Cerebral venous thrombosis

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especially prothrombin mutation, APA, antithrombin deficiency

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Cerebral venous thrombosis in women on oral contraceptives

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especially prothrombin mutation

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Inferior vena cava, renal venous, mesenteric venous, portal and hepatic venous thromboses

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especially APA, cancer, antithrombin deficiency

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Recurrent superficial thrombophlebitis

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Factor V Leiden, Protein C or S deficiency)

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Warfarin skin necrosis

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Protein S and C deficiencies (homozygous –Neonatal purpura fulminans

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Unexplained fetal losses

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APA

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What happens to older thrombi?

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Organization
Ingrowth of endothelial cells, smooth muscle cells, and fibroblasts
Recanalization
Capillary channels form trying to re-establish continuity of the original lumen

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Platelet count, bleeding time, PT/PTT are usually normal
Infections (meningococcemia, infective endocarditis, Rocky mountain spotted fever)
Drug reactions
Scurvy, Ehlers-Danlos: defects in collagen
Henoch-Schonlein purpura – systemic hypersensitivity, deposition of circulating immune complexes within vessels and glomeruli (characterized by purpuric rash, abdominal pain, polyarthralgia, and acute glomerulonephritis)
Hereditary hemorrhagic telangiectasia (Weber-Osler-Rendu) – AD, dilated tortuous blood vessels with thin walls
Perivascular amyloidosis

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Bleeding – vessel wall abnormalities

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– caused by autoantibodies (IgG, 90%) to platelets, mostly directed against glycoproteins IIb-IIIa or Ib-IX
- antiplatelet antibodies act as opsonins that are recognized by IgG Fc receptors on phagocytes; leads to increased platelet destruction
-female/male ratio is 3/1; usually under 40 years
petecchiae and ecchymoses, nosebleeds, bleeding gums
-diagnosis of exclusion; PT/PTT normal, platelets decreased and may have large platelets in blood (increased megakaryocytes in bone marrow)
- steroids; splenectomy helps

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Chronic ITP (immune thrombocytopenic purpura)

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Non-specific – spleen, bone marrow, blood
Spleen usually normal size; histo shows congestion of splenic sinusoids with enlargement of splenic follicles associated with prominent reactive germinal centers
Marrow – modest increase in megakaryocytes, some more immature
Blood – abnormally large platelets

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Immune Thrombocytopenic Purpura - pathology

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Also caused by autoantibodies to platelets (IgG Abs directed against GpIIb-IIIa receptors, as in chronic ITP)
– mainly children
- symptoms may occur abruptly often after viral illness (2 weeks before)
- self-limited within 6 months

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Acute ITP

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Originally pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia, transient neuro deficits, and renal failure
deficiency of ADAMTS13 plasma enzyme (acquired or inherited) which normally degrades very HMW multimers of vWF – results in increased circulating vWF multimers which aggregate and cause platelet activation, adhesion, and aggregation
Both are caused by insults that lead to excessive activation of platelets which deposit as thrombi in microcirculation
PT and PTT are normal
Important diagnosis to consider in patient with thrombocytopenia and microangiopathic hemolytic anemia
Rx plasma exchange – removes autoantibodies and provides functional ADAMTS13

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TTP (thrombotic thrombocytopenic purpura

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usually no neuro, prominence of acute renal failure, children (traditional)
Epidemic - associated with E. coli strain O157 which produces Shiga-like toxin that changes endothelial function in some way so that platelets are activated and aggregate (out of circulation)
Non-epidemic - associated with defects in complement factor H, CD46, or factor I (all prevent excessive activation of the alternative complement pathway) and also endothelial cell functions to promote platelet activation
normal ADAMTS13 levels; caused by insults that lead to excessive activation of platelets which deposit as thrombi in microcirculation

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Hemolytic Uremic Syndrome

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Defective adhesion of platelets to subendothelial matrix; AR
Inherited deficiency of platelet membrane glycoprotein complex Ib-IX, receptor for vWF and needed for normal platelet adhesion to subendothelial ECM

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Bernard-Soulier syndrome – defective platelets

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Defective platelet aggregation; AR
Platelets do no aggregate in response to ADP, collagen, epinephrine, or thrombin because of deficiency or dysfunction of glycoprotein IIb-IIIa, integrin which is part of “bridge” between platelets by binding fibrinogen

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Glanzmann thrombasthenia – defective platelets

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Acquired platelet function defect
Potent, irreversible inhibitor of enzyme cyclooxygenase, needed for synthesis of thromboxane A2 and prostaglandins which play important roles in platelet aggregation and release reactions

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Aspirin

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Clotting factor abnormality; not usually petecchiae but more likely prolonged bleeding following surgery or cut
vWf produced by endothelial cells (and megakaryocytes, found in platelet alpha granules) binds to factor VIII and stabilizes it; promotes adhesion of platelets to subendothelial matrix by bridging interactions
Most common inherited bleeding disorder of humans (1% of adults in US); AD, rarely AR; usually mild; epistaxis, menorrhagia, excessive wound bleeding
Type 1 and 3 – reduced quantity of circulating vWF (1 usually mild, AD, whereas 3 is AR and severe)
Type 2 – qualitative defects in vWF (subtypes) – mild to mod bleeding
Platelet count is normal; PT normal, increased PTT; because vWF stabilize Factor VIII, deficiency in vWF leads to decrease in Factor VIII; desmopressin stimulates vWF release (Rx for 1 and 3)

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vonWillebrand Disease

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Most common hereditary disorder associated with life threatening bleeding
Mutations in factor VIII, essential cofactor for factor IX and clotting cascade
X-linked recessive
Less than 1% normal levels of factor VIII = severe disease; 6 to 50% normal levels = mild disease
Easy bruising, massive hemorrhage after trauma or surgery; spontaneous hemorrhage into joints (hemarthroses); no petechiae
PT normal, PTT prolonged
Rx – recombinant Factor VIII; 15% of patients develop antibodies that inhibit factor VIII

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Hemophilia A (Factor VIII deficiency)

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Factor IX deficiency
X-linked recessive
Variable clinical severity
15% - Factor IX present but not functional
PT normal/ PTT prolonged
Rx - infusions of recombinant Factor IX

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Hemophilia B – Christmas disease

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is triggered by (1) release of tissue factor by thromboplastic substances (e.g., placenta, granules of APL, mucin from certain adenocarcinomas) into circulation (2) widespread injury to endothelium
Mostly associated with obstetric complications, malignant neoplasms, sepsis, and major trauma
Consequence: widespread deposition of fibrin in microcirculation which leads to ischemia of susceptible organs and microangiopathic anemia because rbcs squeeze through narrow microvasculature and become fragmented
RX – remove or treat inciting event/underlying cause; transfusions of blood products

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DIC

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Lab findings:
Increased PT/PTT
Decreased fibrinogen
Thrombocytopenia
Presence of fibrin degradation products and d-dimers
Microangiopathic anemia, schistocytes (rbcs damaged by fibrin thrombi

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DIC