Basics of hemostasis pathology

1. DISORDER OF
HEMOSTASIS
DR. ROSHAN KHATIWADA

2. Hemostasis:
• Hemostasis is a precisely orchestrated process involving platelets, clotting
factors, and endothelium that occurs at the site of vascular injury and
culminates in the formation of a blood clot, which serves to prevent or limit
the extent of bleeding.

3. Stages of Hemostasis:
1. Primary hemostasis : Forms a weak platelet plug and is mediated by
interaction between platelets and the vessel wall.
2. Secondary hemostasis : Stabilizes the platelet plug and is mediated by the
coagulation cascade

7. PRIMARY HEMOSTASIS
• Step 1—Transient vasoconstriction of damaged vessel
1. Mediated by reflex neural stimulation and endothelin release from endothelial cells
• Step 2—Platelet adhesion to the surface of disrupted vessel
1. Von Willebrand factor (vWF) binds exposed subendothelial collagen,
2. Platelets bind vWF using the GPlb receptor.
3. vWF is derived from the Weibel-Palade bodies of endothelial cells and alpha-
granules of platelets.

8. • Step 3—Platelet degranulation
1. Adhesion induces shape change in platelets and degranulation with release of multiple mediators.
i. ADP is released from platelet dense granules; promotes exposure of GPIIb/IIIa receptor on
platelets.
ii. TXA2 is synthesized by platelet cyclooxygenase (COX) and released; promotes platelet
aggregation
• Step 4—Platelet aggregation
1. Platelets aggregate at the site of injury via GPIIb/IIla using fibrinogen (from plasma) as a linking
molecule; results in formation ofplatelet plug
2. Platelet plug is weak; coagulation cascade (secondary hemostasis) stabilizes it.

10. DISORDERS OF PRIMARY
HEMOSTASIS
• Usually due to abnormalities in platelets; divided into quantitative or qualitative
disorders.
• Clinical features include mucosal and skin bleeding.
1. Symptoms of mucosal bleeding include epistaxis (most common overall symptom),
hemoptysis, GI bleeding, hematuria, and menorrhagia. Intracranial bleeding occurs
with severe thrombocytopenia.
2. Symptoms of skin bleeding include petechiae (1-2 mm), purpura (> 3
mm),ecchymosis (>1cm) and easy bruising; petechiae are a sign of thrombocytopenia
and are not usually seen with qualitative disorders.

12. • Useful laboratory studies include
1. Platelet count—normal 150000-400000 per microliter ; < 50000 leads to
symptoms,
2. Bleeding time—normal 2-7 minutes; prolonged with quantitative and qualitative
platelet disorders
3. Blood smear—used to assess number and size of platelets
4. Bone marrow biopsy—used to assess megakaryocytes, which produce platelets

14. IMMUNE THROMBOCYTOPENIC
PURPURA (ITP)
• Autoimmune production of IgG against platelet antigens (e.g., GPIIb/llla)
1. Most common cause of thrombocytopenia in children and adults
• Autoantibodies are produced by plasma cells in the spleen.
• Antibody-bound platelets are consumed by splenic macrophages, resulting in
thrombocytopenia.
• Divided into acute and chronic forms:
1. Acute form arises in children weeks after a viral infection or immunization; self
limited, usually resolving within weeks of presentation
2. Chronic form arises in adults, usually women of childbearing age. May be primary or
secondary (e.g., SLE). May cause short-lived thrombocytopenia in offspring since
antiplatelet IgG can cross the placenta.

15. • Laboratory findings include
1. Decreased platelet count, often < 50000 per microliter.
2. Normal PT/FTT— Coagulation factors are not affected.
3. Increased megakaryocytes on bone marrow biopsy
• Initial treatment is corticosteroids. Children respond well; adults may show early response, but
often relapse.
1. IVIG is used to raise the platelet count in symptomatic bleeding, but its effect is short-lived,
2. Splenectomy eliminates the primary source of antibody and the site of platelet destruction
(performed in refractory cases).

16. SECONDARY HEMOSTASIS
• Stabilizes the weak platelet plug via the coagulation cascade
• Coagulation cascade generates thrombin, which converts fibrinogen in the platelet plug to fibrin.
• Fibrin is then cross-linked, yielding a stable platelet-fibrin thrombus.
• Factors of the coagulation cascade are produced by the liver in an inactive state.
• Activation requires:
1. Exposure to an activating substance
i. Tissue thromboplastin activates factor VII (extrinsic pathway).
ii. Subendothelial collagen activates factor XII (intrinsic pathway).
2. Phospholipid surface of platelets
3. Calcium (derived from platelet dense granules)

19. DISORDERS OF SECONDARY
HEMOSTASIS:
• Usually due to factor abnormalities
• Clinical features include deep tissue bleeding into muscles and joints (hemarthrosis)
and rebleeding after surgical procedures (e.g.circumcision and wisdom tooth
extraction).
• Laboratory studies include:
1. Prothrombin time (PT)—measures extrinsic (factor VII) and common (factors II, V,
X, and fibrinogen) pathways of the coagulation cascade
2. Partial thromboplastin time (PTT)—measures intrinsic (factors XII, XI, IX, VIII)
and common (factors [I, V, X, and fibrinogen) pathways of the coagulation cascade

20. HEMOPHILIA A
• Genetic factor VIII (FVIII) deficiency
1. X-linked recessive (predominantly affects males)
2. Can arise from a new mutation (de novo) without any
family history
• Presents with deep tissue, joint, and postsurgical bleeding
1. Clinical severity depends on the degree of deficiency.
• Laboratory findings include
1. Increased PTT; normal PT
2. Decreased Factor VIII
3. Normal platelet count and bleeding time
• Treatment involves recombinant FVIII.

21. HEMOPHILIA S (CHRISTMAS
DISEASE):
• Genetic factor IX deficiency
• Resembles hemophilia A, except FIX levels are decreased instead of FVIII

22. THROMBOSIS

23. Thrombosis:
• Pathologic formation of an intravascular blood clot (thrombus)
a. Can occur in an artery or vein
b. Most common location is the deep veins (DVT) of the leg below the knee.
• Characterized by (1) lines of Zahn (alternating layers of platelets/fibrin and RBCs,
and (2) attachment to vessel wall
a. Both features distinguish thrombus from postmortem clot.
• Three major risk factors for thrombosis are disruption in blood (low, endothelial cell
damage, and hypercoagulable state (Virchow triad)

25. I. DISRUPTION IN NORMAL BLOOD
FLOW:
• Stasis and turbulence of blood flow increases risk for thrombosis.
a. Blood flow is normally continuous and laminar; keeps platelets and
factors dispersed and inactivated.
• Examples include
i. Immobilization—increased risk for deep venous thrombosis
ii. Cardiac wall dysfunction (e.g. arrhythmia or myocardial infarction)
iii. Aneurysm

26. II.ENDOTHELIAL CELL DAMAGE
• Endothelial damage disrupts the protective function of endothelial cells, increasing the risk
for thrombosis.
• Endothelial cells prevent thrombosis by several mechanisms.
a. Block exposure to subendothelial collagen and underlying tissue factor
b. Produce prostacyclin (PGI,) and NO—vasodilation and inhibition of platelet aggregation
c. Secrete heparin-like molecules—augment antithrombin III (ATIII), which inactivates
thrombin and coagulation factors
Causes of endothelial cell damage include atherosclerosis, vasculitis, and high levels of
homocysteine

27. III. HYPERCOAGULATION:
a. Activation of the coagulation system. Example: disseminated intravascular
coagulation.
b. Hereditary or acquired factor deficiencies. Examples: hereditary antithrombin
(ATIII) deficiency, oral contraceptives (estrogen decreases concentration of ATIII;
increases the synthesis of factors I [fibrinogen], V and VIII).
c. Antiphospholipid syndrome. Associated with the presence of lupus anticoagulant
and/or anticardiolipin antibodies.
d. Thrombocytosis (increased platelet count). Etiologies include malignancy and
essential thrombocytosis.

29. EMBOLUS

30. Embolus:
• Detached mass (e.g., clot, fat, gas) that is
carried through the blood to a distant
site.
• Types:
i. Atherosclerotic embolus: Has
cholesterol clefts
ii. Fat embolus
iii. Air embolus
iv. Amniotic fluid embolus

31. Pulmonary Embolism:
• Usually due to thromboembolus; the most common source is deep
venous thrombus (DVT) of the lower extremity, usually involving the
femoral, iliac, or popliteal veins.
• Most often clinically silent because (1) the lung has a dual blood supply
(via pulmonary and bronchial arteries) and (2) the embolus is usually
small (self resolves)
• Pulmonary infarction occurs if a large- or medium-sized artery is
obstructed in patients with pre-existing cardiopulmonary compromise;
only 10% of PEs cause infarction