Pathophys Hematology And Oncology

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1˚ Hemostasis

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1˚ hemostasis= platelet adhesion and aggregation and vessel wall integrity
ie-1st response- form a first ‘glob’ to plug a hole.

Problems= muco-cutaneous bleeding and immediate surgical bleeding

Causes: Isolated Thrompocytopenia: ITP (gpIIb autoantibody), TTP (ADAMS13), DIC (2˚to chronic disease), Glanzmann thrombasthenia (gpIIb/IIIa receptor defect), Bernard Soulier syndrome (Ib/V/IX receptor defect)

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3 actions of platelets:

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1. Adhesion- after exposure of the subendothelium (collagen and vWF) which attract the platelets to bind to the vWF via glycoprotein (gp)-Ib-V-IX
2. Aggregation- binding of platelets to other platelets (Gp IIb/IIIa receptor on the platelet surface binds to fibrinogen which in turn binds to a platelet)-forms the platelet plug. Also the release of granules from platelets. 2 types: _ (factor V, vWF and fibrinogen)and dense (contain Ca2+, ADP, ATP and serotonin)
3. Activation- platelet changes and special phospholipids are expressed on the surface of the platelet- start coagulation cascade

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cell based model of hemostasis

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three phases:
Initiation: occurs in the tissue factor bearing cell (and a little bit of Va) TF binds to circulating VII and activates X. Xa can bind to Va and generate a small amount of thrombin (Factor II) enough for priming. TF-VIIa complex also activates IX
Priming: The small amount of thrombin released is enough to activate the platelets- V in the _ granule is released and expressed on the activated platelet surface. Thrombin 1) releases VIII from its carrier protein vWF 2) activates XI on the activated platelet surface
Propagation: form the fibrin clot. IXa from TFBC migrates over to VIIIa and binds. IXa can also be activated by XIa on the activated platelet surface. IXa-VIIIa together form what is called the Ten-ase (X-ase) complex. Xa binds its cofactor Va forming the prothrombinase complex- activates II(thrombin) resulting in a burst of thrombin that can form the fibrin clot

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Functions of Thrombin

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Procagulant: 1)Aggregate and activate platelets
2)Activate cofactors V and VIII
3)Activate factor XI
4)Cleave fibrinogen to form fibrin
5)Activate factor XIII – cross-linking fibrin and forming a stable fibrin clot
Anti-coagulant- Activate protein C

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2˚ Hemostasis

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2˚ hemostasis= platelet activation and coagulation reactions as well as clot stabilization
ie.- the ‘nice, normal’ clot forms to prevent bleeding for an extended period of time

Problems= muscle hematomas, hemarthrosis and delayed surgical bleeding.

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Mixing Studies

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1st step in working up an abnormal aPTT/PT (deficiency vs. inhibitor)
* 50% presence of a specific clotting factor is enough to fully correct a deficiency.
The process: Two test tubes, one containing the patient’s plasma and the other containing normal pooled plasma (NPP) are mixed together (a 50:50 mix). Then aPPTs are run again to look for correction
Results-
1)Correction= deficiency (patient’s plasma contains 0%, when mixed should be 50% presence, enough to correct the deficiency)
2) Repeate prolonged aPPT= Inhibitor (Lupus Antibody is bound)

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Hemophilia

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Factor VIII and IX, or VWD-type 2N (VIII carrier) deficiency
X-linked disorder
delay in secondary hemostasis:
Joint and muscle bleeding- hemarthrosis
Intracerebral hemorrhage
Delayed post surgical bleeding
Bleeding with trauma

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3 Anti-coagulation mechanisms

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1. Plasminogen is activated by tissue plasminogen activator (tPA) into plasmin, which degrades fibrin
2. Antithrombin III (AT-III) circulates, binds heparan, and inactivates activated serine proteases (Factors XIa, IXa, Xa, and IIa)
3. thrombin (Factor IIa) is activated, binds thrombomodulin and activates Protein C, then C complexes with Protein S on the platelet surface to inactivate Factor Va

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Virchow's Triad with associated causes

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1. Decreased blood flow- Venous stasis, Hyperviscosity, Myocardial dysfunction, pregnancy
2. Inflammation of vessels- Vasculitis, Homocysteinuria (damaging vessel walls), Behçet Disease, Endothelial Damage
3. Hypercoagulitable state- factor V leiden, malignancy, elevated Lp (a), elevated VIII, pregnancy (Estrogen), DIC, Lupus Anticoagulant, prothrombin mutation, Polycythemia Vera, essential thrombocythemia

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Platelet disorders that lead to thrombosis

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DIC (secondary to chronic disese)
HIT (Heparin induced antibody)
Lupus Anticoagulant (antibody to cardiolipan)
Paroxysmal nocturnal hemoglobinuria (complement activation)
Essential thrombocythemia (overproduction)

* all can cause clotting (over activation) or bleeding (consuming faster than producing)

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5 common causes of thrombophilia

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1. Antithrombin III deficiency (don't give Heparin)
2/3. Protein C deficiency and Protein S deficiency (don't give coumadin first)
4. Factor V Leiden (extremely common)
5. Prothrombin 20210 A (twenty two-ten A) mutation

*Thrombophilias are additive- this includes inherited and environment risk factors (smoking, oral contraceptives, plane rides)

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Acute Leukemia

Definition
Clincal Presentation

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clonal, neoplastic proliferation of immature hematopoietic cells characterized by arrested differentiation causing an impaired production of normal blood cells
ALL= kids AML= adults
Clincally: roaring in the ears, diffuse bone pain (esp at night), fatigue, low-grade fever, infections, bruising, bleeding, Hyperviscosity (CHF, blurred vision, etc), gingival hyperplasia
Pancytopenia (or elevated WBC)

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Immunophenotyping (flow cytometry) for Acute Leukemia

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1. Myeloid (AML): CD13, CD33, CD117
2A. T-cell markers (T-ALL): CD2, CD5, CD4, CD8
2B. B-cell markers (B-ALL most common): CD10 (precursor), CD19, CD20
* All leukemias express DR+ except FAB-M3

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Acute Leukemia Prognostic Factors

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1. Cytogenetics-* most important factor
2. WBC at presentation: Higher white count is associated with a poorer prognosis.
3. Age. Younger age is associated with a better prognosis.
4. Subtype of AML/ALL. M3 (Promyelocytic leukemia) is very curable. M6/M7 is rarely curable.
5. LDH is an indirect marker of cell turnover. High values indicate a rapidly proliferating tumor (>700).
6. Expression of early antigens CD34 (stem cell marker/undifferentiated leukemia) and CD 56.
7. Poor initial response to chemotherapy.
8. Gene expression profile.

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Cytogenetics of Acute Leukemia as prognostics

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Good Prognosis (chemo alone)
AML: t(15,17); t(8,21); Inv 16
ALL: hyperdiploidy (>50 chromosomes); t(12,21)

Poor Prognosis (offer bone marrow transplant)
Chromosomes 5, 7, 8, 11, complex cyto, t(9,22)

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Acute Leukemia Tx

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ALL: 2 year of therapy involving 5 drugs
AML: 6 months of therapy involving 2 drugs
* if poor prognostics/no response to Tx consider bone marrow transplant

Complications to Consider:
1. Assume Infection at ANY sign of fever (esp Gram -)
2. Tumor lysis syndrome
3. DIC profile
4. Irradiated blood products (GVHD)

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CML

Definition
Clinical Presentation

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clonal proliferation with NO maturation arrest
Ph+ t(9:22)

Chronic Phase- asymptomatic (4-6 years)
Intermediate Phase- unstable WBC count (1 year)
Acute Leukemia- conversion to acute form

Clincal Presentation: Fatigue, early siety (spenomegaly)

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CML Tx

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All based upon eradication of bcr-abl

1. Targeted Tx (Gleevec, etc-resistance exists)
2. Chemo/INF-A
3. Bone Marrow Transplant

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B Cell Maturation and markers

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B cells arise from the lymphoid progenitor and progress from pre-B cells (CD 10), to B lymphocytes (CD20 and CD22 only), to plasma cells (CD138).

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Burkitt's Lymphoma

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proliferative

t(8;14)- myc oncogene and immunoglobulin heavy chain enhancer gene.

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Follicular Lymphoma

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Anti-apoptotic- slow growing

t(14;18)- anti-apoptotic gene and immunoglobulin heavy chain enhancer gene.

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Mantle Cell Lymphoma

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Proliferative

t(11;14) cyclin D1 (cell cycle regulatory gene) is overexpressed

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Diffuse Large B-Cell Lymphoma Tx

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Tx Rituximab (targets CD 20)

genotype for germinal vs active

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Multiple Myeloma

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Plasma Cell Proliferation- IgG

Bone pain, renal dysfxn, amyloid, M protein, etc

t(11;14) (4;14) and (14;16)= aggressive phenotypes

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MGUS

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3-5% of all 60-70 yr olds

low plasma count and an M-spike with NO symptoms

Risk of progression to MM is only 1% per year

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Waldenstroms macroglobulinemia

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Plasma cells proliferation- IgM
Most rare B cell lymphoma

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Bleeding Time

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Platelet function

Prolonged-
1. Platelets below 20,000,
2. Aspirin intake
3. uremia
4. VWD
*2-4 platelet count is not diminished but bleeding time is prolonged due to dysfunctional platelets

*ITP has marked decline in platelet count, but bleeding time is not prolonged

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Prothrombin time (PT)

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extrinsic pathway

Isolated PT= Factor VII

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Activated partial thromboplastin time (aPTT)

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intrinsic pathway

Isolated aPTT= Factors 8 or 9

* can also include Factors 11 (asymptomatic) and 12 (hypercoaguable!!)

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Thrombin/reptilase time

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activates thrombin and determines the rate of reaction of cleavage of fibrinogen to fibrin

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Clot stability tests

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measure the time it takes for a clot to dissolve.

Clot instability= Factor XIII

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Ristocetin platelet aggregation studies

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Ristocetin should cause spontaneous platelet aggregation

Does not occur= VWD

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B Symptoms

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night sweats
unexplained high temperatures (fever)
weight loss