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INTRODUCTION TO THE BLEEDING DISORDERS ("HEMORRHAGIC DIATHESES")

Your lecturer has no interest in presenting one more overview of the clotting cascades, the activation of platelets, or the mysteries of endothelium. We'll look today at diseases that affect one or more of these. I promise to keep it simple.

One more time... THE REAL CLOTTING CASCADE (i.e., how it works in life most of the time)

All diseases of inadequate hemostasis have spontaneous bleeding (petechiae, purpura, mucous membranes, GI bleeding, hematuria, into joint spaces, or even just unusually heavy periods) and/or excessive bleeding after trauma or surgery.

The range is from lethal diseases (factor VIII:C deficiency, Bernard-Soulier's, Glanzmann's) to non-diseases (factor XII deficiency, many von Willebrand's).

Three groups:

• Increased vascular fragility


• Platelet deficiency or dysfunction


• Problems with the clotting factors

TESTING HEMOSTASIS

Platelet count: reference range is 150,000 to 400,000 (or 450,000 or 350,000);

* Above 350,000 is uncommon and may reflect the action of cytokines in patients with inflammation and/or mild iron deficiency.

Platelets rise at ovulation, and fall low at the start of menstruation.

{14727} finger-stick blood; platelets clumped!

Bleeding time: checks both quantity and functional quality of platelets.

Before standardization, "normal was 2-9 minutes".

Ivy: Stab with a 3 mm lancet. Normally bleeds 3-6 minutes.

Template: Use a standard spring-loaded razor device that produces a 1 mm deep, 3 mm long incision. Normally bleeds 6-10 minutes; probably this is longer than the Ivy time since platelet recruitment is slower for this tiny wound.

{14117} bleeding time, step 1
{14120} bleeding time, step 2
{14123} bleeding time, step 3
{14126} bleeding time, step 4
{14129} bleeding time, step 5
{14132} bleeding time, step 6
{14135} bleeding time, step 7
{14138} bleeding time, step 8
{14141} bleeding time, step 9
{14144} bleeding time, step 10

Thrombin time (TT): checks factor I (fibrinogen) activity

Prothrombin time (PT): checks activities of factors I, II, V, VII, and X

Today you will get your prothrombin time reported as an INR ("international normalized ratio"), which is the ratio of the time for patient and control to the power determined for that lot of reagent (the ISI, or international sensitivity index):



* You'll try to maintain your patients on coumarin in various ranges (2.0-3.0 to prevent deep vein thrombi in patients at high risk; 2.5-3.5 for patients with mechanical heart valves; etc., etc. Chest 108(S): 231, 1995).

Activated partial thromboplastin time (aPTT): checks activities of factors I, II, V, VIII, IX, X, XI, XII. It is prolonged when one of these drops below about 30% of healthy.

Clot retraction: checks factor I, platelet count, and a particular platelet function (missing in Glanzmann's disease)

Urea solubility: checks factor XIII ("fibrinoligase", cross-links fibrin strands, rendering the clot insoluble)

Fibrin degradation products (FDP, "fibrin split products", FSP, X-Y-D-E): increased levels suggest ongoing fibrinolysis by plasmin, particularly in disseminated intravascular coagulation (DIC); these are also likely to be elevated when a large thrombus is present.

D-dimer: From broken-down clots that have been crosslinked. Once billed as "a more specific test for DIC", it's now clear that D-dimer is elevated whenever there is intravascular thrombolysis, whether from DIC or big thrombi.

Platelet aggregation studies: testing response to ADP, thrombin, collagen, serotonin, catecholamines, and thromboxane A₂ -- all "platelet agonists". Platelet function testing explained: Arch. Path. Lab. Med. 126: 133, 2002. Remarkably accurate new assays: Am. J. Clin. Path. 122: 178, 2004.

Mixing studies: Mix the patient's blood half-and-half with blood from somebody who is healthy. If the patient has an antibody against a clotting factor, the tests will remain abnormal. If the patient is missing something important, the tests will become normal.

Tip: Get a functional, rather than an immune-based, assay for proteins C, S, AT-III, etc., etc. Some people's factors may contain a mutation that renders them non-functional but still demonstrable by immune methods.

CD40 ligand: Platelet protein; up-and-coming test to show that there's platelet activation in the body, i.e., this patient's chest pain is likely to turn into an infarct (NEJM 348: 1104, 2003).

Thromboelastrography: Blood is rotated in a cup and a sensor measures how fast it clots and how tough the clot is. Probably the best way to check for hypercoagulable blood in trauma patients -- i.e., who needs clotting factors, who clearly doesn't (J. Trauma 67: 266, 2009).

INCREASED VASCULAR FRAGILITY ("nonthrombocytopenic purpuras", etc.): bleeding problems despite normal platelet count, bleeding time, PT, aPTT, TT, FDP)

Bleeding from fragile vessels, with normal platelets and coagulation, is seldom serious.

Massive bleeding is rare. Vascular fragility is more likely to cause skin bruises, dependent petechiae, gum bleeding (eating, toothbrushing), hematuria, nosebleeds, GI bleeds.

Causes include:

INFECTIONS (meningococcemia, gonoccemia, scarlet fever, SBE, other forms of sepsis, rickettsial disease, the many viral hemorrhagic fevers, Ebola being only one) that particularly damage endothelium. The bleeding usually won't be massive, but it warns of grave systemic illness.

Meningococcal sepsis also depletes protein C selectively. The resulting microthrombi cause gangrene of the extremities. The meningococcus also damages the endothelial cells using a toxin, to prevent the white blood cells from docking on the adhesion molecules (J. Cell Bio. 173: 454, 2006).

AMYLOIDOSIS

COLLAGEN PROBLEMS: scurvy, Ehlers-Danlos syndrome ("the human pretzel"), Cushing's syndrome, osteogenesis imperfecta (patients do not convert reticulin to regular collagen normally), hereditary hemorrhagic telangiectasis (Osler-Weber-Rendu disease; patients have an abnormal type III collagen or some related mutation and some vascular malformations that bleed easily), "old age" ("senile purpura")

{05940} scurvy, gums
{38195} scurvy case, bone

IMMUNE-COMPLEX DEPOSITION IN VESSEL WALLS: serum sickness, Henoch-Schonlein purpura, cryoglobulinemia, wonder drugs (the usual cause of "leukocytoclastic vasculitis", lots of living and dead neutrophils around the cutaneous vessels, which in turn is the common cause of "palpable purpura" on the skin)

{12261} erythema multiforme case with purpura
{12262} erythema multiforme case with purpura
{12529} erythema multiforme case with purpura

* MIND PHENOMENA (Gardner-Diamond autoerythrocyte sensitization / psychogenic purpura, religious stigmatization; do you believe in this stuff? I don't know....)

Gardner-Diamond ("autoerythrocyte sensitization", "psychic purpura") is the strangest of the lot -- platelet aggregation studies are abnormal, and asensation of warmth followed by painful bruises appear around the body. Unlike other folks, the lesions are reproduced by intradermal injection of the patient's own washed red cells. It responds to removal of the stressors. See Eur. J. Haem. 65: 144, 2000. Some say it's a factitious disease -- I doubt this since platelet functions do seem abnormal.

As noted, the usual platelet and coagulation tests are normal. (Capillary fragility tests using blood pressure cuffs, the old "tourniquet test", etc., are not very useful.)

REDUCED PLATELET NUMBER ("THROMBOCYTOPENIA"): Ped. Clin. N.A. 51: 1109, 2004, lots more

Platelets are the first line of defense against bleeding, plugging up little holes in capillaries (PRIMARY HEMOSTASIS) in seconds. Of course, they also help initiate coagulation (to solidify the blood before it gets through the bigger holes), and eventually become an important component of most clots. The activating of the clotting factors, which takes minutes, is called SECONDARY HEMOSTASIS.

Think of platelets as little band-aids that turn into bricks (fibrin's the mortar).

Excessive bleeding due to platelet disorders is apparent almost immediately after trauma. Excessive bleeding due to coagulation factor deficiency becomes apparent only after a few minutes.

Thrombopoietin ("megapoietin") finally cloned and characterized: Nature 369: 533, 1994; Proc. Nat. Acad. Sci. 91: 11104, 1994; Proc. Nat. Acad. Sci. 94: 4669, 1997.

Your lab can now assay thrombopoietin: Eur. J. Hem. 61:119, 1998.

Thrombopoietin is now being used to make people make extra platelets prior to chemotherapy; these are harvested and re-transfused (Lancet 359: 2145, 2002).

* And we now have eltrombopag, an non-peptide oral thrombopoietin-receptor agonist, that's finding use in chronic ITP (Lancet 373: 641, 2009) -- works for leukemia and myelodysplastic syndrome too of course (Blood 114: 3899, 2009.

Here's how the feedback works: Something in the body produces a constant amount of thrombopoietin, and most of it gets sopped up by the circulating platelets. Any that's left-over stimulates the production of more platelets.

* Thrombin does some carving on thrombopoietin and perhaps this is why more platelets are produced when you start clotting. Stay tuned.

Always order a CBC, which includes a platelet count, on anybody who seems seriously sick.

Thrombocytopenia is said to be present when platelet count is less than 100,000/mcL. Platelet problems are often heralded by petechiae on the skin and mucosal surfaces.

Bleeding after trauma (surgery, etc.) can be a problem when platelet count is below 40,000/mcL.

Spontaneous bleeding likely to occur only when the platelet count is below 20,000 or so. (Petechiae and purpura randomly over the skin, blood blisters in the mouth, GI, GU, CNS bleeding.)

{11526} hemorrhage in thrombocytopenia (* "Sweet's syndrome" case)

Severe spontaneous bleeding may be expected when count gets below 10,000/mcL.

Causes of thrombocytopenia are many.

• Decreased production...
  • tumor in bone marrow, myeloproliferative disorders, myelofibrosis

{13805} giant platelets, myelofibrosis case

• megaloblastic anemias


• AIDS (megakaryocytes may express CD4 and be destroyed)


• certain hereditary syndromes (notably the autosomal dominant May-Hegglin, with only a few, bizarre, giant platelets, plus Dohle body-like structures in neutrophils)


• sepsis (this remains a major mystery of medicine)


• * paroxysmal nocturnal hemoglobinuria (the mutation may also affect megakaryocytes)


• * Wiskott-Aldrich (platelets will also be tiny)


• predictable drug reactions (i.e., cancer chemotherapy, two of the worst are * cytosine arabinoside and * daunorubicin)


• idiosyncratic drug reactions (notorious are binge drinking and thiazide diuretics; the latter can produce a mild thrombocytopenia that persists for weeks following withdrawal of the drug)
• liver failure at the VERY end (no thrombopoietin)


• Increased destruction...

  • autoimmune disease ("idiopathic thrombocytopenic purpura", SLE)
  
  
  • drug-antibody complexes on platelets (many possible offenders; the best-known are gold, sulfa, quinine, and quinidine; prove it by a dramatic return in platelet count following withdrawal of offending drug)
  
  
  • isoimmune (fetal-maternal incompatibility, post-transfusion)
  
  
  • DIC (including sepsis, burns, snakebite, etc.)
  
  
  • thrombotic microangiopathies (thrombotic thrombocytopenic purpura, hemolytic uremic syndrome)
  
  
  • large spleen syndrome ("hypersplenism", as in cirrhosis, rheumatoid arthritis, Gaucher's disease)
  
  
  • massive hemorrhage (patient getting transfused with blood but physician forgets to give platelets)
  
  
  • heparin-induced thrombocytopenia / thrombosis
  This dread "white clot disease" is caused by autoantibodies against a complex of heparin and platelet factor 4 (Blood 94: 208, 1999); we are seeing less nowadays thanks to the less-immunogenic low-MW heparin; update Arch. Path. Lab. Med. 126: 1415, 2002. Testing for the antibody: Am. J. Clin. Path. 128: 150, 2007.
  
  
  • * decompression sickness (platelets aggregate on the bubble surfaces)

• * Not counted:
  • Satellitism (some people have an antibody that makes platelets stick to each other and to neutrophils if they sit in EDTA and/or other anticoagulants too long: Am. J. Hem. 70: 246, 2002; Am. J. Clin. Path. 115: 376, 2001; NEJM 338: 591, 1998)
  
  
  • Clumping (clumsy venipuncture -- by the way, platelets are always clumped on a fingerstick smear)

  Tip: If you see only a few platelets and many of them are large, the patient is probably turning out platelets very rapidly (i.e., they have not fully separated from one another), i.e., they are being destroyed peripherally. Of course, to be sure, you may want to do a bone marrow exam. If platelets are being destroyed peripherally, you will see many, young megakaryocytes with hypo-segmented nuclei.

  * Pitfall: When remission of a leukemia is being induced, the fragmentation of the white cells may result in fragments that are interpreted by the automated cell counters as platelets, disguising a serious thrombocytopenia (Arch. Path. Lab. Med. 123: 1111, 1999).

Patients with platelet abnormalities have increased bleeding time, normal PT, aPTT.

To distinguish a thrombocytopenia of decreased production (few or non-maturing megakaryocytes) or increased destruction (increased megakaryocytes), examine the bone marrow.

If platelets are rapidly being destroyed and the marrow is making them overtime, giant platelets are often abundant in the peripheral blood.

ISOIMMUNE / ALLOIMMUNE THROMBOCYTOPENIA

Neonatal: Fetal-maternal incompatibility, analogous to hemolytic disease of the newborn.

Mother's IgG antibodies against some specific platelet antigen on baby's platelets causes them to be destroyed. Read all about it: NEJM 337: 32, 1997.

Post-transfusion: After a PlA1-negative patient receives someone else's PlA1-positive platelets (to which the patient must be already sensitized), she starts destroying her own platelets. (Immune complexes adsorbed to the patient's platelets are probably the cause.)

IDIOPATHIC THROMBOCYTOPENIC PURPURA ("ITP", autoimmune thrombocytopenic purpura, "ATP", etc.,review Blood 113: 6511, 2009):

ACUTE ITP: a disease of children, most often following a viral infection.

Platelets become coated with antibodies (probably not anti-platelet autoantibodies, but immune complexes from the viral illness) and get eaten by the RE system.

Thrombocytopenia in AIDS results from this mechanism, and/or autoantibodies against IIb-III and/or HIV attacking megakaryocytes that are positive for CD4

* HIV-positive patients often make a unique antibody against GPIIIa that fragments platelets without complement involvement. Patients who have hepatitis C on board seem to get it worse, as a result of molecular mimicry: Blood 113: 4086, 2009.

CHRONIC ITP: a disease of adults, especially those with autoimmune disease. True anti-platelet antibodies are present, and platelets are destroyed by the RE system as in acute ITP.

Chronic ITP tends to be mild and presents only a small risk to life. Some physicians do not treat unless counts fall below 30,000 (Lancet 359: 4, 2002).
* Romiplostim ("Nplate"), the molecule that stimulates the thromboplastin receptor, seems to work wonders for chronic ITP: Lancet 371: 395, 2008; Blood 114: 3748, 2009.
The stuff seems to cause increased marrow reticulin but this is reversible on discontinuation (Blood 114: 3748, 2009).

Drugs for chronic ITP, including the thrombopoietin-receptor agonists romiplostim and eltrombopag: Lancet 373: 1562, 2009.

Both types have increased IgG in the platelet fraction. Splenectomy is necessary in some cases. (The spleen makes much of the offending antibody, and it eats most of the sensitized platelets.)

* Future pathologists: Want to know if the surgeon got the entire spleen, and didn't leave an accessory spleen or a bit of spilled spleen tissue behind? Fully-splenectomized patients have Howell-Jolly bodies in their circulating red cells!

THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP; review Am. J. Clin. Path. 121 S: S-89. 2004)

This is a dread disease that kills young adults. It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (i.e., DIC), fever, transient neurologic defects, and renal failure.

Microthrombi occur in the arterioles and capillaries of most organs. They're almost always worst in the heart. They are made of loose "hyaline" aggregates of platelets and von Willebrand's factor, with just a little bit of fibrin.

The pathophysiology yielded up its secrets with the discovery of von Willebrand factor cleaving protease (which removes big aggregates of von Willebrand's factor from the blood).

People with acquired TTP have an autoantibody against this protease (NEJM 339: 1585, 1998). This explains the success of plasma exchange in treating the disease, and now of added rituximab (Am. J. Clin. Path. 125: 592, 2006).

Familial TTP (* "Schulman-Upshaw") features a familial deficiency of this protease (NEJM 339:1578, 1998; gene ADAMTS-13 Nature 413: 438, 2001; Blood 102: 1148, 2003; Blood 104: 2081, 2004; there's more to the story as the deficiency is prothrombotic but not sufficient to make the disease inevitable Blood 107: 3161, 2006, which make sense because if it were, the children would not be born ).

TTP may be secondary to lupus (must be the autoantibody... treating it South. Med. J. 101: 943, 2008), HIV-infection (South. Med. J. 88: 82, 1995), * ticlopidine (as after coronary stenting, JAMA 281: 806, 1999) and others.

Today you may diagnose it by the finding of severe thrombocytopenia plus microangiopathic hemolysis without alternative explanation; your pathologist can help by finding big aggregates ("ultralarge multimers") of vWF in the blood (Am. J. Clin. Path. 121-S: S89, 2004). Once uniformly fatal, the disease is now being cured. The treatment involves administration of fresh-frozen plasma (Lancet 345: 224, 1995), up to complete plasma exchange.

HEMOLYTIC-UREMIC SYNDROME is a mostly-kidney microangiopathy caused by damage (bacterial toxins, medications, pregnancy) to the endothelial cells. Thrombocytopenia occurs but is less prominent. The little thrombi are composed primarily of fibrin, the endothelial cells are damaged and swollen, and there is molecular debris along the basement membranes of the renal microvasculature. Compare-and-contrast with TTP: Arch. Path. Lab. Med. 127: 834, 2003. Alphabet soup: "Unlike DIC, in both HUS and TTP, the PT and PTT will usually be normal." More about this under Kidney.

* "Thrombotic microangiopathy of unknown cause" is seen especially in patients given such treatments as mitomycin, cyclosporin, tacrolimus (South. Med. J. 101: 744, 2008), heavy-duty chemotherapy, quinine (with the antiplatelet syndrome), organ transplants, or total-body radiation. The microthrombi can appear either systemically (mimicking TTP) or mostly in the kidney (mimicking HUS), often long after exposure. The mechanisms aren't known, but probably involved damage endothelium. It would seem wise to not to call these either TTP or HUS.

{08059} petechiae on heart, leukemia case
{21433} petechiae from football mouth-guard, no hemostasis problem

DEFECTIVE PLATELET FUNCTION (normal platelet count, prolonged bleeding time)

What platelets do for you:

Step 1: ADHERE (i.e., to collagen and basement membrane)

Step 2: RELEASE their ADP (makes platelets work better) and their catecholamine (local vasoconstriction) and their thrombin (activates fibrin directly)

Step 3: AGGREGATE (i.e., stick tight and recruit more platelets, due to ADP)

Step 4: FUSE tight to fibrin and each other, to seal the leak

Step 5: RETRACT (i.e., pull the clot tight)

Note that as long as platelet release and fibrin production are reasonably normal, there will not be bleeding from small nicks (i.e., shaving) even in patients with hemophilia.

* Lab workup of platelet disorders: Arch. Path. Lab. Med, 126: 133, 2002.

Hereditary:

DEFECTS OF PLATELET ADHESION

Bernard-Soulier disease (the most common of the several "giant platelets syndrome"; Arch. Path. Lab. Med. 131: 1843, 2007)

An autosomal recessive, thankfully-uncommon, severe bleeding disorder.

Giant, useless platelets that won't stick to the subendothelium; severe bleeding.

There is a deficiency of certain glycoproteins (* notably Ib; genes vary) that bind the factor (VIII:R) that enables platelets to interact to collagen.

Stem cell transplantation for cure: Ann. Int. Med. 138: 79, 2003.

There is a mild dominant allele (big platelets, lowish counts, harmless): Blood 97: 1330, 2001; Am. J. Med. 112: 742, 2002. Some Bernard-Soulier heterozygotes have huge platelets but no problems (Blood 97: 1330, 2001).

THere are at least 11 other genetic giant platelet disorders. All are even less common than Bernard-Soulier. The curious may read

Von Willebrand's disease (see also below): Review Medicine 76: 1, 1997.

An autosomally inherited, qualitative or quantitative lack of Von Willebrand's factor.

There is no aggregation in response to ristocetin, but there is normal aggregation in response to epinephrine, collagen, ADP.

The platelet defect is corrected by normal or hemophilic ("factor VIII-deficient") plasma.

DEFECTS OF PLATELET SECRETION (of prostaglandins and ADP, the "release reaction"): various "aspirin-like" hereditary diseases too rare and complicated to outline here!

* Storage-pool disease. Some folks have absent granules. Gray platelet syndrome: No alpha granules. Hermansky-Pudlak: No delta granules. Chediak-Higashi: Diminished granules and some platelet dysfunction. Leave this arcane stuff to the hematologists.

* Hermansky-Pudlak syndrome: Any of several genetic diseases with defective production of melanosomes, absent delta platelet granules, and lysosomes (Blood 96: 4227, 2000; Blood 107: 4857, 2006; Am. J. Path. 166: 231, 2005); patients are albinos and in many variants, pulmonary fibrosis causes death.

* Gray-platelet disease: No granules. Autosomal-variable, and a bleeding problem. Thankfully rare. See Blood 98: 1382, 2001.

Of course, today we induce platelet dysfunction using meds such as aspirin and the ADP-receptor binders for our coronary artery patients (update NEJM 361: 940, 2009).

Pseudo-Gray Platelets
Virginia
Good pictures


DEFECTS OF PLATELET AGGREGATION

Thrombasthenia (Glanzmann's disease, formerly "tired platelet syndrome"):

An uncommon, autosomal recessive, severe bleeding disease.

Platelets fail to aggregate on an un-anticoagulated peripheral smear, with ADP, collagen, epinephrine, or thrombin. Clot retraction is also absent. (They lack the integrin glycoprotein GPIIb-IIIa that binds fibrinogen which in turn bridges platelets. Pathologists stain this with CD41 and CD61 -- megakaryocytes failing to stain well indicates Glanzmann's. Read all about it: Am. J. Hum. Genet. 53: 140, 1993; molecular biology Blood 90: 669, 1997.) An acquired autoimmune variant exists (J. Ped. 144: 672, 2004).

This is the same glycoprotein complex that abciximab / tirofiban / eptifibatidetherapy is directed against in acute coronary disease: Am. Heart J. 138: S16 & S24, 1999.

The popularity of these medications is probably going to drop, since nowadays their tendency to cause heavy-duty bleeding possibly outweighs their benefits (JAMA 297: 591, 2007).

* Gene therapy for Glanzmann's works in mice: Blood 106: 2671, 2005.

Acquired defects:

Aspirin permanently inhibits cyclooxygenase (by acetylating it), preventing production of thromboxane A2 and producing an acquired secretion defect that lasts for the life of the platelet (a platelet lives about 9 days)

The other NSAIDS temporarily block cyclo-oxygenase.

* All about NSAIDS and platelets: Am. J. Med. 106 (5B): 25S, 1999.

In uremia, there is a complex platelet defect reversed by dialysis, which may be due to * phenol and/or * guanidinosuccinic acid.

* Alcohol enhances the effect of aspirin on platelets. During an alcoholic binge, the platelet numbers drop; during alcohol withdrawal, there is a rebound thrombocytosis that can produce a stroke if somebody is predisposed.