THROMBOCYTOSIS

Thrombocytosis is a platelet count above 400,000/mcL.

It may occur as a rebound after severe bleeding, after surgery or sepsis, following splenectomy, or just runs in the family, or is part of the disease in iron deficiency (common, but no one knows why), carcinomatosis, or * Hodgkin's disease.

Thrombocythemia is a sustained platelet elevation over 800,000/mcL. Unless there's some other obvious explanation, this indicates some myeloproliferative disorder (leukemia, polycythemia vera, early myelofibrosis, etc).

If there is no other known illness, it is called "essential thrombocythemia", a myeloproliferative disorder, and the patient may have either thrombi or platelet insufficiency. Today's criteria allow the diagnosis if the platelet count is consistently over 600,000 and a workup (including marrow tap) shows no cause (especially, no bcr/abl): Ann. Int. Med. 139: 470, 2003. This will soon be replaced by clonality assays (Blood 101: 3294, 2003). Even then, it's likely to remain asymptomatic for a long time, and is seldom lethal (Am. J. Med. 117: 755, 2004). Update Mayo Clin. Proc. 80: 97, 2005. (* New remedy works wonders: anagrelide. Many current references. Hydroxyurea plus low-dose aspirin may work even better: NEJM 2005: 353, 2005.)

{24786} essential thrombocythemia
* {13748} "megakaryocytic myelosis"

ABNORMALITIES IN COAGULATION FACTORS (abnormal PT, aPTT, TT, and/or FDP; usually normal platelet count and bleeding time)

Deficiencies of all of the clotting factors have been described.

For each, the deficiency can be mild or severe, the protein can be absent or just defective, or the deficiency may be due to an inhibitor (antibody, etc.) against it.

Deficiencies may be hereditary or acquired:

Hereditary deficiencies involve a deficiency of a single factor.

Acquired deficiencies (except those due to an autoantibody) involve several factors

Deficiency of vitamin-K-dependent factors (neonates, malabsorption, heavy antibiotics, coumarin therapy, bad liver trouble)

Remember the body requires vitamin K so that the liver can make gamma-carboxyglutamic acid, present only in factors II, VII, IX, and X.

* Of these, factor VII is the first to go, so the defect will appear initially in the extrinsic pathway, i.e., abnormal PT.

Heparin therapy potentiates antithrombin III, so heparin indirectly inactivates thrombin.

* The thrombin time estimate for fibrinogen is useless in the heparinized patient, so the lab uses snake venom ("Russell viper venom time, RVVT") instead of thrombin.

"Circulating anticoagulant" is the common term for any abnormal protein, not part of the normal clotting-anti-clotting systems, that interferes with coagulation.

Such a protein may be either an autoantibody against a clotting factor, or an inhibitor of one or more steps. Both are common enough in systemic lupus, rare in other people.

Disseminated intravascular coagulation (all factors consumed, as are platelets.)

Patients with coagulation factor deficiencies rarely have spontaneous petechiae or purpura. Instead, they get ecchymoses or hematomas after minor injury that the platelets don't handle. Bleeding for days after tooth extractions, or bleeding into joint spaces (hemarthroses) are common.

DEFICIENCIES OF FACTOR VIII COMPLEX

Factor VIII:C (procoagulant) is the clotting factor required to activate factor X in the intrinsic pathway. It is coded on X-chromosome.

It circulates bound to VIII:R (von Willebrand's factor, made in endothelium and megakaryocytes) which is required for the interaction of platelets with subendothelial collagen and also protects VIII:C from destruction.

VIII:R is required for platelet aggregation by ristocetin.

Von W's factor is a tumor marker for Kaposi's sarcoma (of endothelial origin) and other angiosarcomas.

CLASSIC HEMOPHILIA ("factor VIII deficiency", hemophilia A, "royal blood"): Review of the two major hemophilias: Lancet 361: 1801, 2003.

Sex-linked recessive deficiency of factor VIII:C.

This is a mild, moderate, or severe bleeding disorder affecting 1 in every 5000 men.

Female carriers may have mild disease due to unlucky lyonization (Blood 85: 599, 1995).

Severe cases have maybe 1% or less activity of the healthy protein.

Hemarthroses, especially in the knees, are excruciatingly painful and lead to crippling early in life. No one knows why bleeding in the knees and other big weight-bearing joints is so common in the hemophilias.

At least in the developed nations, most of these men now lead near-normal lives thanks to recombinant factor VIII.

Fewer than 10% of patients are ever troubled by autoantibodies against factor VIII, but when it does happen, it can be a disaster. Why?

* Managing these patients is expensive but works; keys are activated factor VII (Blood 102: 2358, 2003) and inducing tolerance (Blood 96: 1698, 2000).

Gene therapy for hemophilia should be routine in the next decade or so. It has already worked in animals, and a phase 1 study (UC Davis) has some hopeful results (Sept. 2003: Blood 102: 2038, 2003). An earlier attempt using fibroblasts, without even a virus, raised levels; the trick is to get the fibroblasts to continue making the factor VIII for more than a few months(NEJM 314: 1735, 2001).

Hemophilia Large hemorrhage KU Collection

* Hemophilia in crown prince Alexis enabled the charlatan Rasputin to gain much control of the Russian royal family, a disaster that helped lead to the Bolshevik revolution. Two modern physicians examine what really happened: Am. J. Surg. 145: 193, 1983 (great read). Hemophilia in the royal families of Europe: Br. J. Haem. 105: 25, 1999.

VON WILLEBRAND'S DISEASE ("pseudohemophilia")

Probably the commonest inherited hemorrhagic disorder. It involves a qualitative or quantitative deficiency of VIII:R/vWF (thus often also low VIII:C as it's not protected) and/or the platelet factor to which it binds (* glycoprotein Ib α).

Thus there is prolonged bleeding time and, in severe cases, some prolongation of aPTT. And of course the platelets don't stuck together well; in particular, they fail to respond to ristocetin, which should active the vWF receptors on platelets ) resulting in the vWF gluing the platelets together. If you don't understand this, please review it.

Autosomal inheritance varies according to subtype: dominant (asymptomatic to moderate forms) or recessive (severe forms; carriers are asymptomatic).

All the von Willebrands' syndromes are autosomal dominant and relatively mild, with the exception of type III, which results from two doses.

Easy...

I. Enough vWF is not made. This is by far the most common. At least half these people are completely asymptomatic (Blood 101: 2089, 2003)

II. Mutant vWF

IIa. Failure to cleave multimers, so the vWF binds poorly to platelets)
IIb. Large complexes bind inappropriately to platelets, which are then cleared; thrombocytopenia; increased reactivity to ristocetin; don't use desmopressin (why not?)
IIn. Binds to platelets much better than to VIII; low VIII levels

III. Two doses, severe illness

In a woman with heavy periods and a normal pelvic exam, von Willebrand's is quite likely: Lancet 351: 485, 1998.

Remember that von Willebrand's factor is an acute phase reactant, so levels may be normal during other illnesses.

Sex hormones (especially estrogens) partially correct the molecular deficiency in some types, so the disease often gets better at puberty. The management of von Willebrand's disease, especially before surgery, used to be based on administering factor VIII concentrates, which are full of good vWF multimers. Treatment was revolutionized in the 1980's by the discovery that desmopressin (!) raises vWF levels.

Acquired von-Willebrand's has at least three etiologies.

It is common in the presence of aortic valve stenosis (!) The shear forces somehow damage the factor multimers so that they don't stick well to collagen or platelets, even though they still bind well to factor VIII. NEJM 349: 343, 2003.

Think also of autoantibodies, and adsorption to the surfaces of tumor cells (Mayo Clin. Proc. 77: 181, 2002).

FACTOR IX DEFICIENCY (hemophilia B, Christmas disease)

Sex-linked recessive deficiency, often even more severe than, but otherwise similar to, classic hemophilia. One man in 25,000 is affected. Again, the joint disease is the most troublesome feature from day to day.

Mr. Christmas was the first patient discovered to have factor IX deficiency.

Like patients with factor VIII deficiency, most of these people now enjoy near-normal lives, the recombinant protein having been introduced in 1999. Only about 3% make troublesome antibodies against factor IX.

* Attempts at cure with gene therapy are of course ongoing. The trick is getting the transfected cells to pump the stuff out (Blood 101: 2963, 2003).

* Factor V deficiency: parahemophilia.

* Alpha-2 plasmin inhibitor (antiplasmin) deficiency has been described; you remember this is the stuff that binds up any active plasmin that makes it into the flowing blood (Br. J. Hem. 114: 4, 2001). The treatment is to administer tranexamic acid or epsilon-amino caproic acid, both of which prevent binding of plasminogen to fibrin.

Lots more.

HYPERCOAGULABLE BLOOD: "Thrombophilia"; "hypercoagulopathy". Not rare, but tends to get overlooked. Big reviews: Am. J. Med. 116: 81, 2004; Ann. Int. Med. 138: 128, 2003; Postgrad. Med. 101(5): 249, May 1997. Lab screening: Am. J. Clin. Path. 108: 434, 1997.

Remember these causes:
Hereditary: As you'd expect, all except hereditary hyperhomocysteinemia are autosomal dominant, with double-dose being more severe. This list is most-common to least-common.
• * Prothrombin G20210A


• Factor V Leiden (R506Q activated protein C resistance = APC resistance)


• Protein C deficiency


• Protein S deficiency


• Antithrombin III deficiency


• * Sticky platelet syndrome (controversial entity described in the 1970's and promoted by two independent thinkers today)


• methylene tetrahydrofolate reductase deficiency (hyperhomocysteinemia)


• Factor XII deficiency (paradoxical)


• * Dysfibrinogenemia (mutant fibrin is not removed by plasmin), plasminogen deficiency, tPA deficiency (remember tPA comes from intact endothelium; why is this good?); all are thankfully rare; Arch. Path. Lab. Med. 126: 1387, 2002


• * Heparin cofactor II (Arch. Path. Lab. Med. 126: 1394, 2002)

Acquired:

• Antiphospholipid antibody syndromes


• Anticardiolipin antibody


• Lupuslike anticoagulant


• Trousseau's (paraneoplastic)


• Hyperhomocysteinemia (folic acid deficiency)



* Prothrombin G20210A is a point mutation affecting 2% of people; it renders blood slightly more coagulable. It is insufficient, by itself, to cause thrombosis. It can be detected only by DNA testing and only recently have people started talking about this being worthwhile (Arch. Path. Lab. Med. 126: 1319, 2002, contrast Mayo Clin. Proc. 75: 595, 2000).

Protein C deficiency (Blood 85: 2756, 1995) and protein S deficiency are relatively common; 1 person in 300 is heterozygous for lack of protein C. (The most severely affected homozygotes get lethal purpura fulminans as babies.) You know that thrombomodulin on intact endothelium activates protein C (why is that good?), and that S and C work together to destroy Va and VIIIa. These patients (notably the homozygotes, protein C deficient heterozygotes are at around 8x increased risk, homozygotes 80x: Lancet 341: 134, 1993) clot their blood too readily, and are prone to pulmonary emboli and so forth. Both protein S and protein C are vitamin K dependent proteins. Thus the benefits of warfarin therapy are probably limited; this is recently supported (Arch. Int. Med. 157: 2227, 1997); since warfarin depresses protein C levels before it depresses II, VII, IX, and X, these people may actually develop skin necrosis from taking the medication; see Ob. Gyn. 90: 671, 1997; Br. J. Surg. 87: 266, 2000.

Hereditary deficiency of antithrombin III is quite common. When it's just a matter of too little being produced (* type I AT3 deficiency), there's an increased risk especially for deep vein thrombi. When it's mutated (* type II AT3 deficiency), perhaps the patient will not respond to heparin (which works by enhancing the effect of normal AT3).

We've already probed the mysteries of antiphospholipid antibody syndrome (Blood 86: 617, 1995; Am. J. Med. 100: 530, 1996; mega-review Lancet 353: 1348, 1999; Arch. Path. Lab. Med. 126: 1326, 2002).

This features:
• tendency to venous and arterial thrombi;


• paradoxical prolongation of PTT (usually, by rendering calcium unable to participate in the activation of X; a better screen is RVVT)


• miscarriages



Two different types of antiphospholipid antibodies are described:

"lupuslike anticoagulants", relatively uncommon; specific assays exist but are tricky, and most often it'll be diagnosed presumptively by finding that adding extra phospholipid returns the clotting time to normal (* future pathologists: use diluted russell viper venom);

"anticardiolipin antibody", common, especially serious if longstanding and IgG; a simple ELISA assay makes the diagnosis

Should you anticoagulate them all (NEJM 332: 993, 1995)? Give them low-dose aspirin? Do nothing unless they're very sick (Am. J. Ob. Gyn. 176: 1099, 1997)? Nobody knows yet what's best.

Indeed, we still don't know why people with antiphospholipid antibody get hypercoagulable blood in the first place.

Right now, it seems that the antibodies activate endothelial cells (Circulation 99: 1997, 1999).

we're discovering that many of them also make autoantibodies against proteins C and/or S, and the autoantibody itself may induce TF on the surfaces of monocytes, etc. (Lancet 350: 1491, 1997).

Antiphospholipid antibody
Lost baby
Pittsburgh Pathology Cases


"Activated protein C resistance" is usually caused by a particular point mutation of factor V (V Leiden). It is a common, infamous cause of thrombosis, pulmonary emboli (NEJM 336: 399, 1997; about half of young folks with "unexplained" DVT's have it), second-trimester miscarriage / preterm birth (Lancet 358: 1238, 2001), and accelerated atherosclerosis (NEJM 332: 912, 1995).

* Future pathologists: You'll diagnose this using PCR and/or discovering that adding activated protein C to the tubes doesn't double the PTT. Assays Arch. Path. Lab. Med. 126: 577, 2002.

This factor V resists the anticoagulant effect of protein C (J. Lab. Clin. Med. 125: 566, 1995). This was recognized in 1995 as the most common of the then-five known major hypercoagulability syndromes, affecting maybe 3% of the public.

A major 1998 study found no benefit from long-term anticoagulation of V-Leiden people (BMJ 316: 95, 1998.)

Not surprisingly, V-Leiden is a significant coronary risk factor: Am. Heart J. 147: 897, 2004.

Stay tuned: Hyperhomocysteinemia resulting from any of several kinks in methionine metabolism, or perhaps even just lack of folate in the diet (stay tuned), is now known to be a serious risk factor both for accelerated atherosclerosis and venous thrombi. Update Arch. Path. Lab. Med. 126: 1367, 2002.

Homocysteine damages the endothelium, and does various things to various coagulation factors that are presently being worked out.

Mild forms may be extremely common (Lancet 345: 902, 1995; NEJM 334: 759, 1996; Am. J. Clin. Path. 108: 115, 1997). fortunately, you can treat it with vitamin B₁₂ and folic acid.

* Lupus anticoagulant, factor V Leiden, prothrombin G20210A, and protein S deficiency seem to place a woman at increase risk for fetal loss: Lancet 361: 901, 2003.

You are already familiar with hypercoagulable blood as a complication of cancer, notably adenocarcinomas, notably those of the pancreas ("Trousseau's other sign"). A full cancer workup is probably NOT worthwhile after an episode of primary deep vein thrombosis: NEJM 338: 1169, 1998.
The definitive cause of Trousseau's remains to be discovered. "Cancer procoagulant A", described a decade ago as a cysteine protease, still awaits definitive characterization (Arch. Bioch. 428: 131, 2004).

A major piece of news is that the hereditary thrombophilias are serious risks for clots in the spiral and intervillous arteries of the pregnant uterus. This in turn places the pregnancy at risk for severe pre-eclampsia, abruption, fetal growth retardation, and stillbirth (NEJM 340: 9, 1999.)

Uh... Please don't work up thrombophilia immediately after the acute episode. The labs will be off (why?)