I.  Normal Hemostasis – highly simplified version

A. intact – in addition to structural integrity, the lining of the system namely the , produces a number of molecules that interact with platelets, coagulation and and cause vasoconstriction

B. Primary hemostasis (immediate control of bleeding) – normal platelets in adequate numbers, leading to their:

  1. adhesion  – platelet glycoprotein receptor to von-Willebrand factor (vWF) attached to collagen in the subendothelial matrix
  2. aggregation  -platelet fibrinogen receptor to fibrinogen
  3.   – these proteins are involved recruiting additional platelets (ADP, serotonin), adhesion (fibronectin, thrombospondin), vasoconstriction (thromboxane) smooth muscle cell proliferation (PDGF)

                  4. coagulation support  – supplies phospholipid surface for

C. Secondary hemostasis (long term control of bleeding)-normal coagulation mechanism – series of proteins and tissue factor(s) some with reacting in cascade fashion, ultimately leading to fibrin generation and reinforcement of platelet plug

1. Extrinsic and intrinsic systems – useful in interpreting clotting test but clinically not fully relevant.  For example, deficiencies of factors XII and XI frequently do not result in clinical bleeding. Generation or exposure of tissue factor at damage site initiates the clotting pathway.

2. Interaction with platelets – surfaces of activated platelets amplify coagulation cascade

D. modulating mechanisms to prevent generalized thrombosis

1.  and endothelin (vasoconstriction) opposed by prostacyclin (PGI2) and nitric oxide (vasodilitation)

2. Xa and (IIa) opposed by heparin-antithrombin III

3. protein C, protein S, thrombomodulin oppose VIIIa and Va

4. tissue factor opposed by an inhibitor (TFPI)

E. – required for re-establishing , plasmin activated by such molecules as tissue plasminogen activator (t-PA) can lyse fibrin and fibrinogen.  Antiplasmin molecules such as plasminogen activator inhibitor (PAI) and a2-plasmin inhibitor modulate this system.

 

II.  Tests commonly used to evaluate bleeding disorders (by no means all)

A. prothrombin time (PT) -extrinsic, may be expressed in seconds (time from adding of tissue factor to whole plasma to fibrin formation), percent of normal, or as ratio related to normal- INR (international normalized ratio) – in addition to evaluating factors in the pathway, it is used to monitor coumadin therapy

B. partial thromboplastin time (PTT) – in addition to factors it is used to follow heparin therapy but not low molecular weight heparin

C. thrombin time (TT)- measures conversion of fibrinogen to fibrin – prolonged when fibrinogen level down or abnormal or when inhibitor present

D. fibrinogen level – useful to detect conditions that consume it such as DIC

E. fibrin split products, D dimer – elevated when plasmin degrades fibrin again such as DIC

F. Factor XIII – only factor not evaluated by PT and PTT – therefore if you have a case of a bleeder with normal PT and PTT, measure it

G. bleeding time, 1cm 1mm  = 9 minutes, used in evaluating platelet functions of adhesion, release and aggregation – hard to standardize and its value is being questioned.  It may be useful when von Willebrand’s disease (vWD) is suspected. It is not a good predictor for bleeding with surgical procedures.

H. platelet count, aggregation (for qualitative defects), ristocetin assays (evaluates vWF and platelet interaction)

I. peripheral smear – shapes of red cells and platelets can be a clue for underlying bleeding problems

III.  Symptoms and Signs

A. petechiae

B. purpura

C. ecchymosis

D. abnormal bleeding

1. may lead to significant secondary symptoms, e.g. stroke.

2. defect in primary hemostasis – usually leads to mucous membrane bleeding, e.g.-gingival bleeding, epistaxis

3. defect in secondary hemostasis -usually associated with severe bleeding following surgery or trauma or tooth extraction.

E. history should include:

1.  recurrent bleeding since childhood (after injuries, circumcision, dental extraction),  family history of bleeding – these suggest inherited coagulation factor deficiencies, onset later in life suggests an acquired problem

  1. alcohol and drug history, look especially for aspirin containing over the counter drugs.
  2. other diseases that can interfere with platelets and coagulation cascade such as liver disease, malignancies, connective tissue diseases, infections eg AIDS

F. hypercoagulable states – thrombosis in atypical sites.

IV.  Some examples of problems involving each of the above systems

A. Vascular purpuras

1.  Leukocytoclastic vasculitis – immune complex deposition in blood vessels leads to damage by complement and neutrophils – associated with a number of diseases and drugs

2.  Excessive corticosteroids

a. Cushing’s syndrome

b. exogenous

3.  Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)-inherited telangiectases of mucous membranes leading to bleeding from mucous membranes -e.g., epistaxis,  gastrointestinal bleeds, gingival bleeds

4.  Vitamin C. deficiency

a. bleeding gums common, perifollicular hemorrhage

B. Platelet disorders

1.  Normal platelet count – 200,000 – 400,000/mm3

2.  Quantitative problems

a. thrombocytopenia – low count

b. risk of bleeding increased when count falls to  50,000/mm3, severe bleeding associated with counts below 20,000/mm3

3.   Decreased production

a. bone-marrow suppression -radiation, drugs

b. bone-marrow infiltration – leukemias,  granulomatous diseases, myelofibrosis

4.   Increased destruction

a. idiopathic (or autoimmune) thrombocytopenic purpura (ITP/ATP)- can be acute (usually children) or chronic (adults), immune mediated destruction of platelets. Associated with a variety of infections including HIV, systemic autoimmune diseases such as lupus, malignancies but 50% have no associated factors. Treatment – steroids, other immunosuppressive drugs,- IVIg, splenectomy in severe cases.  Avoid ASA and NSAIDs.  With HIV – HAART.

b. drugs -heparin, gold, quinine, quinidine, cocaine -associated antibodies, GPIIb-IIIa antagonists (used in coronary syndromes)

c. thrombotic thrombocytopenic purpura(TTP)- one of the microangiopathy syndromes that includes thrombocytopenia, hemolytic anemia, neurologic abnormalities, fever, occasional renal failure.  A platelet activator factor or damage to endothelial cells  may initiate it. Coagulation proteins not activated.  Has high mortality without therapy.  Mortality significantly reduced over last few  years .Adult hemolytic uremic (renal failure) syndrome (HUS) is a variant and has a more variable course.  In children it is associated with enteric infections.  Therapy of choice is plasma exchange with fresh frozen plasma.

d.  HELLP syndrome – hemolysis, elevated liver enzymes, low platelets in pregnancy – delivery of fetus is cure

e. Disseminated intravascular coagulation (DIC) (see below)-excessive consumption of platelets by fibrin clots (coagulation proteins are consumed). Has many causes – eg sepsis, malignancies, obstetrical complications, trauma.

f. Hypersplenism – an enlarged spleen (many causes) can sequester platelets and other cellular components of blood.

5.   Increased production – thrombocytosis

a. primary

b. secondary – many causes, malignancies most common

c. patient may have both bleeding ( following tooth extraction, into soft tissue) and thrombotic (arterial or venous, strokes) problems.

6.   Qualitative problems- platelets not functioning properly.

a. drug induced- ASA, NSAIDs, antibiotics

b. malignancies

c. uremia

d. liver disease

e. congenital

 

C. Coagulation system

1.   role of vitamin K- procoagulants II VII IX X, also anticoagulants protein C and protein S – diet, absorption, storage – note that factor five is not vit K dependent

2.   role of liver – all procoagulants are produced by liver except for von Willebrand’s factor (vWf) which is produced by megakaryocytes and endothelial cells

D. Examples of

1.   Hemophilia  – decrease in coagulation factors (VIII-A, IX-B). Normal hemostasis requires 25% factor activity, however significant bleeding starts at 5% or less.

a. inheritance- x-linked, thus males predominate.

b. symptoms – bleeding, hemarthroses especially in weight bearing joints.

c. management- replace factor, fibrinolytic inhibitor, dental work should be done by dentist experienced in dealing with these patients.

2.  Inhibitors of coagulation factors.

a. usually IgG antibodies, may appear from factor infusion (hemophilia), or spontaneously e.g. malignancies, collagen vascular diseases.

b. inhibitor screen test – 1:1 mixture of patients plasma with normal plasma corrects PT or PTT when factor is low but will not correct if inhibitor is present

3.  Von Willebrand’s disease

a. vWf (von Willebrand’s factor) allows platelets to adhere to each other and to injured endothelium, also stabilizes factor VIII. Thus symptoms relate to a combination of factor VIII and platelet dysfunction.  Several variants have been identified.  Probably the most common of the hereditary coagulation disorders.

b. symptoms- varies with type from post surgical (or trauma) bleeding to spontaneous mucosal bleeds ( oral, epistaxis, GI, GU).

c. management- vWf rich-factor VIII concentrate for active bleed. Desmopressin acetate causes release of vWf from endothelial stores and useful for short term therapy, intravenously or nasal spray form.

4.   DIC – (see above) initiated by pathologic generation of thrombin. It activates factors V, VIII, platelets leading to their consumption. Also creates fibrin degradation products, inhibitors of normal hemostasis.

a. symptoms- mostly bleeding, organ dysfunction, skin infarction

b. treatment- treat underlying disorder.

5.   Liver disorders – lack of factors

6.   Drugs – coumadin, heparin, fibrinolytic agents.

E.Hypercoagulable states

1.   Causes include antiphospholipid syndrome, antithrombin III deficiency,  protein C and S deficiency.

2.   Clinically the patient will have recurrent thrombosis in atypical sites without the usual underlying causes, often in young otherwise healthy individuals.

3.   Treatment – usually some form of anticoagulation.