IM Sheet #7 By Natalia

by **Sura** 11/12/2011, 2:49 pm

http://www.mediafire.com/file/24m4bbmt1p9mrj4/bleeding1.docx

by **Shadi Jarrar** 23/12/2011, 8:27 pm

Bleeding disorders

Hemostasis

Normal hemostasis is vital for prevention of blood loss, but controls are necessary to limit coagulation to the site injury. The hemostasis system is vital protective mechanism that is responsible for preventing blood loss by sealing sites of injury in the vascular system. However, hemostasis must be controlled so that blood does not coagulate within the vasculature and restrict normal blood flow.

The endothelial cells of intact vessels prevent thrombus formation by secreting tissue plasminogen activator (t-PA) and by inactivating thrombin and adenosine diphosphate (ADP).This normal inhibitory mechanism prevents spontaneous coagulation that may occur inside the vascular system.

Hemostasis proceeds in two phases: primary and secondary hemostasis.

Primary hemostasis occurs immediately after endothelial disruption ( few seconds after endothelial injury ).

Primary hemostasis is characterized by vascular contraction, platelet adhesion and formation of a soft aggregate plug. It begins immediately after endothelial disruption. Injury causes temporary local contraction of vascular smooth muscle. Vasoconstriction slows blood flow, enhancing platelet adhesion and activation.

Adhesion occurs when circulating von Willebrand factor(vWf) attaches to the subendothelium. Next, glycoproteins on the platelet surface adhere to the sticky von Willebrand factor(vWf). Platelets collect across the injured surface. These platelets are then activated by contact with collagen. Collagen-activated platelets form pseudopods, which stretch out to cover the injured surface, and bridge exposed fibers. The collagen-activated platelet membranes expose receptors that bind circulating fibrinogen to their surfaces. Fibrinogen has many platelet binding sites. An aggregation of platelets and fibrinogen build up to form a soft plug. Platelet aggregation occurs about 20 seconds after injury.

Primary hemostasis occurs within first (1-2 min.) after endothelial injury , after that secondary hemostasis takes place. Mainly secondary hemostasis guarantees that there will not be farther blood loss.

Secondary hemostasis is responsible for stabilizing the soft clot and maintaining vasoconstriction.

Vasoconstriction is maintained by platelet secretion of serotonin, prostaglandin, and thromboxane.

The soft plug is solidified through a complex interaction between platelet membrane, enzymes, and coagulation factors. This leads to formation of permanent plug.

Secondary hemostasis involves the activation of the coagulation cascade.

The cascade model consists of sequence of steps where enzymes cleave proenzyme to generate the next enzyme in the cascade.

This cascade consists of the extrinsic and intrinsic pathways, which merge into common pathway.

Common pathway is responsible for activation of prothrombin into thrombin, which cleaves fibrinogen into fibrin, which becomes cross-linked to form the permanent plug.

There is a control mechanism for each step, each activated factor have another factor that helps in the activation of the next step. There is an inhibitory mechanism in coagulation cascade, which makes thrombosis not become uncontrolled mechanism.

*Any tissue injury leads to activation of intrinsic pathway and extrinsic pathway.*

Common pathway leads to the activation of factor X that comes from extrinsic or intrinsic pathway.

Then factor X activated to Xa (a means active form)

In association with activated factor V_{a ,}factor X_a converts prothrombin into thrombin then thrombin converts fibrinogen into fibrin. Fibrin in association with factor X_a becomes cross linked and form permanent fibrin clot.

Fibrinolysis is a process that prevents blood clots from growing and becoming problematic.
Tissue plasminogen activator (t-PA) is the agent that convert plasminogen to the active plasmin, thus allowing fibrinolysis to occur.

Note. We have to know everything about Extrinsic and intrinsic pathways.

-In extrinsic pathway the main player is factor VII

-intrinsic pathway of coagulation : a sequence of reactions leading to fibrin formation, beginning with the contact activation of factor XII, and resulting in the activation of factor X to initiate the common pathway of coagulation

**This factors was discovered in 1960 (in vetro not in vivo)

When the scantiest studied this model, they discovered some defects in coagulation cascade,

Eg. In patient with factor XII deficiency, we expect them to have severe bleeding because all coagulation pathways will be affected but in fact this is not true (this patient will not have serious bleeding problem)

But the patient who have Haemophilia A or B will have severe bleeding more than the patient who have factor XII deficiency … This means that coagulation cascade is true in vitro. But not necessarily in vivo.

Note: Haemophilia B is a blood clotting disorder caused by a mutation of the Factor IX gene, leading to a deficiency of Factor IX

Haemophilia A is a deficiency in clotting factor VIII

** cell based model of coagulation .

Cell based of coagulation requires the participation of two different types of cells, platelets and tissue factor bearing cells.

All evidence to date indicates that the same relevant initiator of coagulation in vivo is tissue factor .

Cells expressing tissue factor are generally localized outside the vasculature.

In vascular system, there is no tissue factor bearing cell or if there is any, it is in inactive form.

When plasma comes into contact with tissue factor bearing cell,

activated factor VII (VII_a ) makes a complex with exposed tissue factor.

The tissue factor (VII_a)complex activate more factor (VII) as well as factor IX and X, which in turn cleave prothrombin to thrombin.

* What do we have to know about the common factor of coagulation cascade?

We have to know the common factors that are produced in liver because the patients who have liver diseases are expected to have low amount of factors and increase in bleeding tendency.

Patients with platelet diseases also have bleeding tendency.

***If we want to do dental procedure we have to do

Patient evaluation:

The most important thing in patient evaluation is history.

History is an essential part and almost any patient with bleeding tendency will give clue if history was undertaken appropriately.

Previous history of bleeding episodes is very important e.g.:

-Epistaxis

-Bruises people with thin skin, fragile superficial veins have more bruises than expected. In those people, small trauma may cause bruises and increase risk in bleeding tendency.

-Bleeding after dental procedure or patient who have a history of bleeding from the gingiva after teeth brush.

- excessive menstrual

- post surgical procedures such as circumcision of children (any bleeding after first day is considered as significant bleeding).

**Family history of bleeding tendencies (because there is many inherited bleeding disorder) is another important factor in patient evaluation.

Consanguinity increase risk to have inherited bleeding diseases.

After patient evaluation, we do screening tests.

Screening test is done if we suspect a hematological disease or if the patient takes medication that may affect hemostasis.

Platelet role:

Patients play a major role in primary hemostasis .

Patient who have platelet problem may bleed immediately after minor injury because they fail to form primary plug.

Platelet malfunction may occur because of two major reasons:

1)Low platelet count ( quantitative defect ): thrombocytopenia

2)Disfunctioning (through normal count, qualitative defect ) platelets: thrombasthenia

Platelet disorders

Platelet disorders result from defects involving primary hemostasis, characteristic physical examination findings include petechiae and purpura, gingival bleeding and epistaxis, excessive menstrual loss .These are the most common types of bleeding encountered with primary hemostatic problems.

Patient with secondary hemostatic problem may have bleeding in deep joint like hemartherosis or bleeding in deep muscles.

petechiae and purpura are superficial bleeding in the skin and they are different in the size.

petechia size up to 0.2 cm, purpura 0.2-1 cm.

patient-with platlet disorder- will have a prolonged bleeding time, and platelet count may be decreased (normal range between 14 000 and 450 000/microl)

Other tests which can be used to assess platelet function in platelet aggregation and platelet function analyzer.

*Bleeding time test found in every hospital but platelet aggregation and platelet function analyzer test are more specialized and available only in special labs.

Bleeding time test:

An incision on the ventral side of the forearm is made, or puncture with a lancet or special needle . The blood pressure cuff is placed on the upper arm and inflated to 40 mmHg. A lancet or scalpel blade is used to make a shallow incision that is 1 millimeter deep on the underside of the forearm.

A standard-sized incision is made around 10 mm long and 1 mm deep. The time from when the incision is made until all bleeding has stopped is measured and is called the bleeding time. Every 30 seconds, filter paper or a paper towel is used to draw off the blood. The test is finished when bleeding has stopped completely

bleeding will stop normally it shouldn't exceed (9-9:30 ) min, if it become more than this mean that there is increase in bleeding time.

Thrombocytopenia

Thrombocytopenia is defined as a platelet count of less than 140000/ microl-

-Patient will complain of signs and symptoms of bleeding mostly in the mucocutaneous part .

-Lab tests will show prolonged bleeding time. -

-Prothrombin tim(P T) and activated partial thromboplastine time (aPTT) will be normal.

Causes of Thrombocytopenia

1)Pseudothrombocytopenia. It is the most common cause.

It is not true Thrombocytopenia,

it is a rare condition in which platelet counts are reported to be low, often <10 000 per μL, yet no hemorrhagic tendencies are present. This condition involves platelet aggregation in vitro.

To know the true result, we put sample under blood film and we will see blood clut, or we count number of platelet manually not with automated machine by this ways we know that it's not true Thrombocytopenia .

2)Immune Thrombocytopenia purpura :

Bone marrow capability to produced normal number of platelet , but they will destruct peripherally by autoantibody.

Female have more tendency to this autoimmune disease.

And it divide it into acute and chronic, if it continues for more than 6 mounts, ,it's called chronic, the acute one which is more common .

3) Gestational Thrombocytopenia: ( Thrombocytopenia associated with pregnancy).It is benign condition ,it's etiology is not well understood, and in this case Thrombocytopenia will be modest (don't go blow 100 000)

4)Hypertensine disorder of pregnancy (eclampcia, preeclampsia) . They associated with severe Thrombocytopenia. It can be life threatening .

5)Thrombotic Thrombocytopenia purpura, it is condition associated with Thrombocytopenia (and increase risk of thrombosis)

the problem is genetic, there is abnormal large willebrand factors and this leads to increase hemostasis and increase thrombosis inside the vessels, and this cause is fatal if we don't treat it. Mortality rate around 90% ,but with treatment, morality rate will decrease to 10-15% and it's rare condition, but it causes severe Thrombocytopenia.

6)Vitamin B12 deficiency, cause modest Thrombocytopenia

7)Leukemia

8)Viral infection ( e.g. HIV infection either in acute or chronic stage),CMV, Epstein-Bar virus can also cause Thrombocytopenia

9)Drug induce Thrombocytopenia

**So thing that cause severe Thrombocytopenia (lower than 50 000 ) are thrombotic Thrombocytopenia purpura ,drug induced Thrombocytopenia, hypertensive disorders of pregnancy .

other things associated with modest Thrombocytopenia and don't go blow 50 000

**We can do dental surgery only if platelet count are more than 50 000.

**If the problem in platelet function or qualitative we can't do any procedure.*

**In case of high risk of bleeding surgeries (e.g. neurosurgical surgeries) a platelet count of at least 100 000 is required.

Common drugs associated with Thrombocytopenia

Quinidene is the most common related to Thrombocytopenia.

Carbamazepine , Valproic acid ,Ranitidin, cimetidine can also cause Thrombocytopenia.

Heparin causes Thrombocytopenia in different way from the other drugs.

Chemotherapeutic agents cause suppression of the bone morrow .So they cause Thrombocytopenia, anemia, and leukopenia.

-Heparin induced Thrombocytopenia: it is immunological condition, where autoantibody affecting the platelet, and this can be tested by platelet factor test.

Although there is thrombocytopenia ,there is an increased risk of thrombosis.

It is common condition ,from 100 patient on heparin ,you can see 10-15 patient have thrombocytopenia.

After 14 days of taking heparin, thrombocytopenia began.

There are 2 types :

Type 1 causes modest thrombocytopenia ,but it isn't related to antibodies and do not need intervention. we just stop heparin and platelet number will return to normal .

Type 2 is immunological reaction.

Thrombasthenia (qualitative platelet disorder )

The underlying etiology is an abnormally functioning platelets in spite of normal count.

Causes:

1)Von Willebrand disease ( the most common inherited to bleeding disorder)

2)Uremia

3)Aspirin and NSAIDS. They are cyclooxygenase inhibitors .Aspirin is irreversible one, NSAIDis reversible .They both inhibit platelet function by decreasing released thromboxone.

4)Glanzmann's Thrombocytopenia. It is autosomal recessive disease. the problem is in the receptors that are found on the platelet surface so platelet aggregation will be decreased or inhibited.

Screening tests

The prothrombin time (PT) measures extrinsic pathway (so it measures function of VII, X , prothrombin and fibrinogen)

Check in warfarin treatment , liver failure (which cause decrease in all coagulation enzymes , vitamin k deficiency, DIC (disseminated intravascular coagulation)

International normalized ration (INR) used to standardized the numbers between laboratories all over the world.

*Normal INR from (1-1.2)

-Warfarin effect on factor that are absorbed under the effect of vitamin K in the intestine ;(IX, X, VII, II) factors .

So factors II, VII, IX, X are affected by vitamin K

X, VII have a big effect on PT and INR warfarin work similar to vitamin. So it will increase in PT and INR reading.

Another screening test is called partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT or APTT) is a performance indicator measuring the efficacy of both the intrinsic and common coagulation pathways.

Detects decrease in XII, XI, IX, VII and antiphospholipids

check in Heparin therapy, hemophilia A and B and antiphospholipid syndrome.

If we suspect that patient have bleeding disorder we ask the patient to do platelet count, bleeding time, PT, aPTT, INR → if they are normal ,this mean there is no hematological abnormality.

Disseminated intravascular coagulation (DIC) is a complex systemic thrombohemorrhagic disorder involving the generation of intravascular fibrin and the consumption of procoagulants and platelet. The resultant clinical condition is characterized by intravascular coagulation and hemorrhage .It will be starts as coagulation but then hemorrhage will dominate.

It is always secondary to an underlying etiology and can be acute or chronic.

Chronic usually doesn't have clinical significant as acute case.

All patients who have acute case admitted to hospital, they have to be admitted because of severe bleeding from every place , any puncture will cause bleeding.

It is fatal if left untreated.

DIC is caused by widespread, uncontrolled and ongoing activation of coagulation, leading to microvascular fibrin deposition , compromising blood supply to various organs.

The ongoing coagulation process will consume clotting factors and platelets leading to prolonged PT, PTT and thrombocytopenia.

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