embryo-outer layer of yolk sac derived from extraembryonic mesoderm is the major site of hematopoiesis

-stem cells migrate into the yolk sac from primitive ectoderm and migrate to liver @ 4-5 weeks-also migrate to spleen, LNs, thymus, BM

-the spleen is exclusively hemotopoietic organ until 14 weeks. At 15-18 weeks it is populated with T cell precursors and at 23 weeks, B cell precursors enter the spleen from B cell regions

Intrinsic (PTT): 8, 9, 10,  11, 12

Extrinsic (PT): 7, 10

Steps taht require Ca²⁺: 11a, 8a, 7a, 5a

inactivate Va and VIIIa and are vitamin K dependent

Factor V Leiden mutation causes resistance to activated protein C

inactivates thrombin IXa, Xa, and XIa

activated by heparin

Heparin

Mechanism: catalyzes the activation of antithrombin III, ↓thrombin Xa. Short  ½ life

Clinical Use: immediate anticoagulation for PE, stroke, angina, MI, DVT. Used in pregnancy. Follow PTT

Toxicity: bleeding, thrombocytopenia, drug-drug interactions. For rapid reversal use protamine sulfate (+charged molecule that acts by binding negatively charged heparin)

Note: LMWH (enoxaparin) acct more on Xa, have better bioavailability and 2-4x longer half-life. Can be given Sub Q w/o monitoring but are not readily reversible

Warfarin

Mechanism: interferes with normal synthsis and γ-carboxylation of vitamin K-dependent clotting factors: II, VI, IX, X and protein C and S. Affects extrinsic Pwy ↑ PT

Clinical use: chronic anticoagulation. CI in pregnancy. Follow PT

Toxicity: teratogenic, drug-drug interactions

Thrombolytics

Streptokinase, urokinase, tPA (alteplase, APSAC (antistreplase)

Mechanism: directly or indirectly aid conversion of plasminogen to plasmin, the major fibrinolytic enzyme, which cleaves thrombin and fibrin clots

Clinical use: early MI, early ischemic stroke

Toxicity: bleeding (CI with active bleeding or Hx of intracranial bleeding, recent surgery, known bleeding diathesis or severe hypertension). Txt ox with aminocaproic acid, an inhibitor of fibrinolysis

Aspirin

Mechanism: acetylates and irreversibly inhibits cyclooxygenase (both COX-1 and COX-2) to prevent conversion of arachidonic acidàprostaglandins. ↑bleeding time. Not effect on PT or PTT

Clinical Use: antipyretic, analgesic, anti-inflammatory, antiplatelet

Toxicology: gastric ulceration, bleeding, hyperventilation, Reye’s syndrome, tinnitus

Clopidogrel, ticlopidine

Mechanism:  inhibit platelet aggregation by irreversibly blocking ADP receptors. Inhibit fibrinogen binding by preventing glycoprotein IIb/IIIa expression

Clinical Use: Acute coronary syndrome, coronary stenting. ↓ incidence or recurrence of thrombotic stroke

Toxicology: neutropenia (ticlopidine)

Abciximab

Mechanism:  Monoclonal antibody that binds to the glycoprotein receptor IIb/IIIa on activated platelets, preventing aggregation

Clinical use: acute coronary syndromes, percutaneous transluminal coronary antioplasty.

Toxicity: bleeding, thrombocytopenia

Cell-cycle specific cancer drugs

Antimetabolites (MTX, 5-FU, 6-MP)àblock DNA synthesis

Etoposideàblock DNA synthesis and synthesis of components needed for mitosis

Bleomycinàblocks synthesis of components needed for mitosis

Vinca alkaloids, paclitaxelàblocks mitosis

Cell cycle nonspecific alkylating agents:

Alkylating agents

Antibiotics (dactinomycin, doxorubicin, bleomycin)

Methotrexate

Mechanism: S-phase-specific antimetabolite. FA analog that ↓DHF-R, ↓dTMP and ↓ DNA and protein synthesis

Clinical use: leukemias, lymphomas, choriocarcinoma, sarcomas, abortion, ectopic pregnancy, RA, psoriasis, chrohn’s disease

Toxicity: myelosuppression (reversible with leucovorin (folinic acid) rescue), macrovesicular steatosis in liver

5-fluorouracil (5-FU)

Mechanism: S-phase-specific antimetabolite. Pyrimidine analog bioactivated to 5F-dUMP, which covalently complexes folic acid. This complex ↓ TS, which ↓dTMPàsame effect as MTX

Clinical use: colon Ca and other solid tumors, BCC (topical), synergy with MTX

Toxicity: myelosuppression which is not reversible with leucovorin, photosensitivity. Hand-foot syndrome, can rescue with thymidine